Re: Quick 25D, 1,25D question (but nerdy) - Dura, Pippet

[Guest guest]

Dura - I have tried to make this point, which is documented by

Lemire, here on this board about a dozen times. It just seems to

bounce off.

This enzyme that converts 1,25-D back into it's inactive precursor

allows a body to have a lot of the stuff at inflammation sites,

while the endocrine or serum level remains well-regulated.

In Sarcoidosis, Lemire says, that fails. It's a double-whammy,

because those folks ARE generating a crapload of 1,25-D to try to

contain those granulomas, and when that becomes a losing battle, a

lot of it is left unutilized. But that would not become harmful, if

the body were able to convert it back into the precursor. In some

Sarcoidosis patients, at least, it cannot, and so the local spills

into the serum level and hypercalcemia ensues.

Why the enzyme fails to be generated in adequate amounts is an

intersting question.

Is this a genetic defect related to VDR? It could well be, such have

been documented, and it's worth asking if there are other diseases

like Sarc that have them. But the fact that the intolerance only

shows up in the sickest Sarc patients makes me skeptical that this

is really the issue.

Sarc inflammation in severe cases is compared to leprosy - it's that

out of control. If the body is trying to generate enough D to

moderate that intense an inflammatory response, it's almost like an

RA patient mainlining pharmaceutical D3 - could well stop the joint

inflammation, but it'll be hard to enjoy that while your puking your

guts out and getting calcium deposits here there and everywhere and

otherwise feeling like dog poo.

The rest of this is not in response to Dura, part commentary on MP,

part warm welcome to Pippet.

If there was evidence of D-induced hypercalcemia in Lyme, CFS, FM,

RA, MS, or any of the other diseases the MP purports to treat, it

would be good for all of us to know that. I however spent months

looking for such evidence and found none, and instead noted studies

that at least two of the diseases I just mentioned have studies

showing significant improvements with D supplementation. So does TB,

interestingly enough.

That doesn't prove there aren't non-Sarc patients who share this

problem, it just proves that the claim that this is a ubiquitous

condition among all patients with the diseases I mentioned is badly

at odds with the published data.

I personally know of at least one patient with each of the above-

mentioned diseases who not only tolerates D well but reports

incremental improvements with regular D supplementation. But I don't

think we have enough data to make conclusions about what type of

improvements or exacerbations can result in these various diagnostic

groupings. All data for MS and RA are encouraging, but we're talking

about a modest number of human studies, extending and confirming

more numerous observations from animal models.

" Fatiguing illnesses " is such a weirdly broad category - there are

very few illnesses that fill one with energy and vigor. It only

seems descriptive when applied to diseases where no other symptoms

than fatigue are notable. Very few of the patients I know, including

those dx'd with CFS, fit that description. Symptoms vary in type,

severity, etc, within and between the diagnoses.

I think with the MP there was a gross over-estimation of the deeper,

less superficial similarities, and not just on the part of it's

creators, but those who helped push it from sarcinfo.com with its

more appropriate focus to this much larger population of chronically

ill folk.

So it's very encouraging to hear from Pippet, talking so

thoughtfully about the tricky business of identifying real

commonalities and differences. Welcome, Pippet - I wish you'd been

here when I was well enough to be actively researching, but there's

a lot in the archive site Ken made for us to show you I really did

apply myself to these 1,25-D questions.

Almost bizarrely so, since it hasn't seemed to have much direct

bearing on my own illness. Five months of experimental D-deprivation

accompanied a big escalation in symptoms, but my symptoms have been

escalating for three years now. I'm pretty sure (different than

certain) D supplementation produces a small but noticable decrease

in one type of pain, and when I initiated it and later raised the

dose I got some progress towards a normal body temp (I run 2 - 2.5

degrees lower than before I was ill). There are more observations,

but they're so tentative it seems less than responsible to publicize

them.

Pippet, I hope you'll keep posting here. It's lovely to see those

abstracts! And I bet you have a lot to teach us about Sarcoidosis. I

think its more unique than the mp site acknowledges, but what we

learn about the body in one chronic inflammatory state is bound, at

least in part, to improve our understanding of others.

Plus, Sarc's such an exemplary case of a devastating disease where

origins have been under-investigated, pathogenesis sloppily

characterized, treatment poorly conceived, and infectious origin

prematurely discounted, a person who's been through what I have

can't help but feel a heart connection to its sufferers.

I have a lot of questions which you may be able to help with. One

concerns the accumulated evidence for an infectious origin in Sarc,

and what researchers who pursue this have to say about the nature of

the pathogen. I've read things which characterize Sarc as a

genetically determined, over-aggressive response to innocous

pathogens. Is that more laziness, do you think? I don't have a clue

what the evidence we have about it amounts to.

> > > As I start to take a gander at this literature, one (quick)

question

> > comes to mind: If

> > > 1,25D is over-regulated by macrophages (e.g., not the usual

25D->

> > 1,25D kidney

> > > stuff), that WOULDN'T per se require a concommitant drop in

25D

> > (the " using it up "

> > > hypothesis). Thus, 1,25D dysregulation from inflammation

would exist

> > independent

> > > of any 25D deficiency. In contrast, LOW 25D and HIGH 1,25D

would

> > implicate a

> > > deficiency vs a immune dysregulation, no?

[Guest guest]

Sorry I missed it . I just asked the question since I was just starting

to learn

about this issue and didn't check back through prior posts. But thanks for

confirming

my intuitions -- really, all chemicals are the same in the body in terms the

mechanisms by which they are modulated & regulated. However, I hadn't

(recently)

seen that particular piece of the puzzle mentioned...

sorry again for the required repetition.

> > > > As I start to take a gander at this literature, one (quick)

> question

> > > comes to mind: If

> > > > 1,25D is over-regulated by macrophages (e.g., not the usual

> 25D->

> > > 1,25D kidney

> > > > stuff), that WOULDN'T per se require a concommitant drop in

> 25D

> > > (the " using it up "

> > > > hypothesis). Thus, 1,25D dysregulation from inflammation

> would exist

> > > independent

> > > > of any 25D deficiency. In contrast, LOW 25D and HIGH 1,25D

> would

> > > implicate a

> > > > deficiency vs a immune dysregulation, no?

[Guest guest]

Dura wrote in part: " sorry again for the required repetition. "

My turn to be sorry - I was't annoyed, and you weren't even here as

far as I know back when I was posting that slew of studies, papers

and reviews on 1,25-D issues.

I was just noting, more in a comic mood (which I obviously failed to

convey) the way in which certain things fail to register. I am only

one link in the I & I " D-train " - before I ever posted here on the

subject, had already supplied abundant evidence that the

MP's claims on the subject were inversions of what people who've

spent the last three decades studying the issues have found. I came

along and delivered maybe two or three dozen of what seemed like the

most relevant references. Ken went to town, and did a better job

than I did of compiling the information in one place, using his own

site.

What I should have said to you, Dura, is congrats for finding an

independent reference which mentions exactly the same thing I found

in Lemire's discussion of Sarc.

Just as I meant to congratulate Ken more heartily than I have on

finding that last study, which does indeed show that too little 25-D

can cause the active metabolite to rise (to bring down PTH),

creating the type of " D ratio " that the mp site insists is proof

positive of D-intolerance and Sarc-like disease.

I can't tell you how frustrated I am with MYSELF for being too sick

to go roaming through my nine hundred and one folders of papers and

links to repost source material. If there was frustration in my

post, with an edge to it, that would have been the source.

> > > > > As I start to take a gander at this literature, one

(quick)

> > question

> > > > comes to mind: If

> > > > > 1,25D is over-regulated by macrophages (e.g., not the

usual

> > 25D->

> > > > 1,25D kidney

> > > > > stuff), that WOULDN'T per se require a concommitant drop

in

> > 25D

> > > > (the " using it up "

> > > > > hypothesis). Thus, 1,25D dysregulation from inflammation

> > would exist

> > > > independent

> > > > > of any 25D deficiency. In contrast, LOW 25D and HIGH

1,25D

> > would

> > > > implicate a

> > > > > deficiency vs a immune dysregulation, no?

[Guest guest]

> This enzyme that converts 1,25-D back into it's inactive precursor

> allows a body to have a lot of the stuff at inflammation sites,

> while the endocrine or serum level remains well-regulated.

The enzyme you're talking about is 24-hydroxylase. It doesn't

exactly convert it back to it's precursor 25(OH)D3. It

converts it to 1,24,25(OH)D3. (And while that metabolite is much

less active than its precursor, it does have some activity, so

it's not totally inactive.)

> In Sarcoidosis, Lemire says, that fails. It's a double-whammy,

> because those folks ARE generating a crapload of 1,25-D to try to

> contain those granulomas, and when that becomes a losing battle, a

> lot of it is left unutilized. But that would not become harmful,

if

> the body were able to convert it back into the precursor.

> Sarcoidosis patients, at least, it cannot, and so the local spills

> into the serum level and hypercalcemia ensues.

> Why the enzyme fails to be generated in adequate amounts is an

> intersting question.

24-hydroxylase (CYP24) activity is at the cellular level in tissues,

mainly in the intestines and the kidneys. Thus, 1,25-D that is

produced and present in other tissues, is not as easily subjected to

that enzyme.

> If there was evidence of D-induced hypercalcemia in Lyme, CFS, FM,

> RA, MS, or any of the other diseases the MP purports to treat, it

> would be good for all of us to know that. I however spent months

> looking for such evidence and found none.

You should be looking for signs of hypercalciuria (increased urinary

calcium), not hypercalcemia. For example, in Crohn's disease, one

study has shown that 42% of patients have above normal vitamin D

levels, but increased serum calcium and hypercalcemia was not

present. See:

Gut. 2004 Aug;53(8):1129-36.

Measurement of vitamin D levels in inflammatory bowel disease

patients reveals a subset of Crohn's disease patients with elevated

1,25-dihydroxyvitamin D and low bone mineral density.

On the other hand, in that study, hypercalciuria was found in

Crohn's disease patients, and increased urinary calcium did

correlate with increased serum vitamin D.

The increased serum calcium and resulting hypercalcemia in

sarcoidosis is likely due to the increased vitamin D levels combined

with another factor that is not found in Crohn's disease , i.e. the

increased ACE levels. In sarcoidosis, where elevated serum ACE

occurs, serum calcium and hypercalcemia do coorelate with ACE

levels. See:

Eur Respir J. 1998 May;11(5):1015-20.

Ionized calcium and 1,25-dihydroxyvitamin D concentration in serum of

patients with sarcoidosis.

This correlation is likely an effect which is unrelated to vitamin

D, as a study on sarcoidosis did not show any significant

coorelation between serum ACE and serum vitamin D. The relationship

between ACE and hypercalcemia, could be due to a reduction of renal

functioning, which commonly occurs in sarcoidosis. Decreased renal

functioning does often coorelates with elevated ACE, and it could be

the cause of reduced calcium excretion.

However, FWIW, there is growing evidence that angiotensin II

actually has it's own direct effects on calcium metabolism.

Thus, this could also explain the correlation between serum ACE and

hypercalcemia. See:

Pediatr Nephrol. 2004 Jan;19(1):33-5.

Angiotensin II reduces calcium uptake into bone.

In any event, in Crohn's disease, serum ACE is rarely elevated (and

actually often below normal), so that might explain why

hypercalcemia only occasionally occurs in that disease, while it's

commonly found in sarcoidosis.

Mark

[Guest guest]

Hi ,

I've been following your updates here and have been saddened by the

tests results you'd been getting over the past few months, especially

the brain atrophy. You have a bright mind and write beautifully and I

don't want you to lose that. I see alot of similarities in some of

the neurosarc patients, and neurolyme patients.

I guess most new discoveries have a tendancy to over-correct or

stylize their findings, not unique to the MP, but what I've found is

that it's all par for the course, part of the learning process. As

new pertinent information is discovered, that gets added to the pile,

then integrated into the hypothesis as time reveals where to go from

here.

As I've always said, we won't know what will turn up in time as this

approach becomes a longevity study, possibly in about 7-8 more years.

Only time will tell. Long-term results will give us that answer. As

with anything new, a shortage of data doesn't necessarily mean that

the hypothesis misses the mark.

I have been deeply looking into the Vitamin D topic (as well as other

aspects of these diseases) and will continue to do that wherever I am

for those who can no longer. It is particularly for these people

whose disease continues to progress that I am committed to this

process.

I have been diagnosed with several autoimmune diseases in addition to

Sarc (and know others who have been as well), so I think there is

more cross-over than either we or scientists yet realize.

Hang in there. There are alot of people out there working on it,

Sincerely,

Pippit

> > > > As I start to take a gander at this literature, one (quick)

> question

> > > comes to mind: If

> > > > 1,25D is over-regulated by macrophages (e.g., not the usual

> 25D->

> > > 1,25D kidney

> > > > stuff), that WOULDN'T per se require a concommitant drop in

> 25D

> > > (the " using it up "

> > > > hypothesis). Thus, 1,25D dysregulation from inflammation

> would exist

> > > independent

> > > > of any 25D deficiency. In contrast, LOW 25D and HIGH 1,25D

> would

> > > implicate a

> > > > deficiency vs a immune dysregulation, no?

[Guest guest]

Just a reminder to Dura and Pippet, that all of the old research and

posts about Vitamin-D are available at:

There are dozens (if not hundreds) of good post with references there.

http://cfsgroups.org/discussion/view_category.php?id=12