of iron and MS

[gainsbourg]

Cheers is keen to emphasise that endothelium dysfunction occurs because of iron disregulation and i do not doubt this is possible because excess iron messes with nitric oxide but i am convinced that the damage is mostly due to oxidative stress. When the excess iron reacts with oxygen, free radicals are produced. Although free radicals are essential molecules in the body's metabolism, they can also destroy cells.

We already know something like this is happening in Parkinson's, Alzheimers and Friedreich's Ataxia due to iron problems, so why not MS?

In Parkinson's:

Disrupted iron metabolism and excess iron accumulation has been reported in the brains of Parkinson's disease patients. Excessive iron can induce oxidative stress subsequently causing degradation of nigral dopaminergic neurons.

In Friedreich's:

In Friedreich's, poor metabolism of iron leads to an accumulation in the mitochondria of nerve cells resulting in neuropathy, for example, in the optic nerve.

I know that anaemia is common in MS and that some people with MS actually take iron supplements but I am still convinced that faulty iron metabolism is a very likely candidate for what is behind the neurodegeneration. It may not matter whether iron levels are high, low or normal, it is the metabolism of iron that seems to be crucial.

Correct iron delivery to the receptor cells in the mitochondria is essential for correct metabolism. The Egyptian study made the discovery that this is going wrong in all types of MS but not in controls. When metabolism goes wrong oxidative stress follows, whether due to imbalance of iron, oxygen, glucose, nitric oxide, insulin or whatever. A faulty carburettor or ignition will make a car sick, regardless of whether gas is high or low in the tank. This fault could be due to a genetic flaw, viral attack, endothelium problems, insulin, stress hormones... the usual selection, but oxidative stress results.

It is interesting that removing iron from mice with EAE ("Mouse MS") supressed the disease and inhibited active T cell function. I know EAE is not 'real' MS but you'd expect removing most of the iron supply would make those little creatures feel a lot worse wouldn't you?

http://msj.sagepub.com/cgi/content/refs/13/9/1118

But it didn't, they got better. They would certainly complain if you removed glucose or oxygen.


gainsbourg

[Terry]

My mother (70 yrs old) has extreme overproduction of platelets. Upon more testing, the doc found that she has NO iron in her bone, yet she still produces red blood cells. (????) It seems that iron can be at different levels in different places throughout the body. The level in the brain is diff from the blood which is diff from the testes in men, which is diff than the level in the bone, are there more? I can't shake the feeling that her issues might teach me something about my MS if I can make sense of it. After all, I am my mother's daughter.
She is being treated with a fairly high dosing of iron for 4 weeks. then back to the doc for more tests.
Makes me want to have a bone marrow biopsy just for curiosity sake.
Has anyone ever thought about seeing a hematologist for their MS?
Terry

[gainsbourg]

Terry,

Sometimes the spleen can produce red blood cells too.

I'd be worried about taking too much iron supplement...the body may have depleted it for a reason.

Without a doubt I would take your mum to see a chinese herbalist or someone who is knowlegable in Ayurvedic medicine, plus take a multivitamin, cut out too much fatty food and cakes and I'm sure she'll be fine. ( I take it she doesn't smoke). Salvia (Dan Sheng) and other herbs like Amrit Kalash can do great things to balance blood and stop the risk of clotting but you need to speak to the experts. Vitamin A in high doses has had surprising results in treating leukemia.

gainsbourg

[MaggieMae]

I'm confused on this iron thing. My husband just had blood work because he is on Tysabri. The nurse told him his iron levels are low and to eat more red meat. Also, a week or so ago, we noticed that his one leg is swollen. We have an appt with his general doctor this week. The nurse said it could be something vascular. Okay! Help me understand. Should I give him iron pills or not? What is the connection? You all understand this much better than I do.

[cheerleader]

I'm confused on this iron thing. My husband just had blood work because he is on Tysabri. The nurse told him his iron levels are low and to eat more read meat. Also, a week or so ago, we noticed that his one leg is swollen. We have an appt with his general doctor this week. The nurse said it could be something vascular. Okay! Help me understand. Should I give him iron pills or not? What is the connection? You all understand this much better than I do.

Oh, goodness. Sorry for your concerns and confusion, Maggie. Go back one page on this thread and read what I wrote. MSers don't need their iron levels raised, it's the transferrin receptor that is off. Have the doc test this before you start iron pills. High transferrin receptor and iron dysregulation could create vascular problems like reflux (as seen in leg petechia, varicose veins and swelling) The blood vessel walls break down and blood is leaks out.

But, his leg swelling may not be vascular. I'd stick to the American Docs Heart Diet, which is low fat, no red meat, high in fruits and veggies. Red meat and saturated fat create inflammation...no good for your husband. You want to calm inflammation and oxidative stress which might be breaking down the blood vessels.

If you want, read my thread on endothelial dysfunction and download the paper...I talk more about the vascular concerns in MS. There's a connection, but docs are confounded by all this, since it doesn't fit with what they've been taught about MS. This might give you more to talk about with your husband's GP. Ours is now behind the program, although she was confused by it all at first.

I hope you figure out his leg issues, and get your husband on the mend.
AC

[cheerleader]

Has anyone ever thought about seeing a hematologist for their MS?
Terry

More and more everyday
Might be a good idea, Terry...if you find someone who understands iron dysregulation and transferrin receptor problems in MS. Hope your Mom's OK.
AC

[jimmylegs]

careful maggie mae, talk this one over with the doc. i don't have time to investigate cheer's line of research in-depth, which i'm sure has some valid points in certain situations - however, please consider also:

-high ferritin can mean a few different things, including deficiency if the underlying iron levels do test low. in that case, you'd want to get the iron values up.
-chronic inflammation can also cause elevated ferritin values that mask deficiency. in that case, you'd want to take on the inflammation, and get the iron up too.

it's certainly not good to overdo iron, but if ferritin is high, you need to be careful to investigate whether it's in fact caused by deficiency, inflammation, OR transferrin receptors being out of whack.

MS is not one size fits all!

[cheerleader]

Jimmy's absolutely right...you want to know the numbers for total iron binding capacity, serum ferritin and serum iron... Especially before starting an iron supplement. Just giving you more questions for the doc.
AC

[Terry]

Sometimes the spleen can produce red blood cells too

Thanks for that., Gainsbourg. I hadn't figured that one out!

Leukemia has been ruled out for my mom, though it will remain a slight risk in the future. No, she does not smoke. I couldn't get her to go to another doc if I tried. She really worried she wouldn't like this one, and luckily, she does. She is dragging her feet to start the iron, though. Im not sure why. She says she's been too busy to go get it. Hmmm. She'd never have known all this was going on except for routine blood work. She feels fine mostly.

I read lots. I don't retain details at all. (Have you noticed?) I cannot tell you in detail why I think this, but "for now" this is what I'm thinking.
Iron deficiency causes absorption and recycling of iron to change. The iron stores should be pretty even throughout the body. Obviously for some it is not. Not for Mom, not for the MS'ers who store extra in the brain. I can't figure out- once we get to this point, whether adding iron will help or hurt. Does something else need adjusted before we add iron? I guess Mom's tests next month will shed a little light.

Does anyone understand Iron-regulatory proteins 1 and 2 (IRP1 and IRP2) ?
Also, this article sure caught my eye.
http://bloodjournal.hematologylibrary.o ... 106/7/2580

Please look at it with me.


I'm long-winded today. Thanks for reading.

Terry

[cheerleader]

Terry...
Iron regulatory proteins seem a wee bit over my head. These proteins function within the cell to regulate iron metabolism. There's an IRP1 and IRP2 and they're made up of amino acids, and they're really small, but large for a protein.

Here's a doc who understands them better than me, and has linked iron dysregulation to MS...James R. Conner of Penn State. He spends all his time researching this and trying to figure out how iron ends up in diseased brains. He believes the proteins may provide a pathway to control this dysregulation. Here's what he says....

Regulation of Expression of Iron Binding Proteins in the Nervous System

The projects in my laboratory are designed to understand the cellular and molecular mechanisms by which cells regulate their iron status. Iron is essential for normal function but at the same time too much iron can be toxic. Therefore cells have an exquisite system for regulating iron levels. When these regulatory mechanims become dysfunctional either through damage, disease or genetic modification cell behavior is abnormal and they sometimes die. Iron imbalance is associated with a prooxidative stress and a proinflammatory environment. Much of our work has focused on mechanisms responsible for regulating iron in the brain. One basic function in which iron is required in the brain is for the production of myelin. We have shown that too little iron during perinatal development will result in hypomyelination. We have also provided evidence that iron can contribute to Multiple Sclerosis (MS). We have established that there is too much iron in the brain in a number of neurological disorders including Alzheimer's (AD) and Parkinson's Diseases (PD). In contrast, there appears to be too little iron in the brain in a disorder known as Restless Legs Syndrome. What is clear from our studies is that optimal brain function requires a tightly regulated iron supply and that the iron must be delivered in a timely manner. To determine the mechanism(s) for brain iron delivery and the regulation of those mechanisms we have focused on a number of mouse and rat mutants as a model of human diseases in which the ability to acquire, moblize or store iron has been disrupted. In the context of these studies we have generated a very promising mouse line in which the gene for the iron storage protein, ferritin, has been deleted. This model is helping to understand the contribution of loss of brain iron homeostatic mechanisms to those changes seen in the brain with AD, PD and MS. In the course of these studies on ferritin, we found that in addition to the cytoplasmic location, ferritin can be found in cell nuclei under some conditions. This observation has led us to basic molecular studies on DNA binding and protection as well as intracellular trafficking of ferritin. The evidence strongly indicates that nuclear ferritin is associated with tumorigenesis. Another avenue under exploration in the context of homeostatic mechanisms is the analysis of gene mutations that lead to disruption of iron status. We have identified mutations in the Hfe gene as a risk factor for Alzheimer's Disease and Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease). The Hfe protein is thought to limit iron uptake by cells and a mutation in this protein may promote inflammation and oxidative stress. We also have a line of research aimed at understanding mechanisms of iron uptake into the brain. This line of research should provide insight into how too much iron can enter the brain in disease states. These studies have led to one particularly novel and important finding of a new receptor in the brain for ferritin. This receptor is expressed only by oligodendrocytes in the brain. We are investigating the possibility that the selective expression of ferritin receptors on oligodendrocytes may have medically important implications for Multiple Sclerosis.

In regard to function of iron in the brain, one area of focus is the regulation of those proteins responsible for iron management in cells. The iron management proteins are regulated by cytoplasmic mRNA binding proteins that are known are iron regulatory proteins. Our project is to determine how the cytoplasmic mRNA binding proteins find their target mRNAs. The outcome of these studies may help us understand how a cell can become iron overloaded but also will contribute significantly to our general knowledge of post-transcriptional gene regulation. One additional approach which is aimed at understanding the function of iron in cells is gene expression profiling. In these studies we have asked the question: "what does it mean to a cell at the molecular level to be iron loaded or iron starved". So far, we have identified a dozen novel genes and a number of genes not previously known to be iron responsive. These data are relevant to cancer and Alzheimer's Disease and Restless Legs Syndrome.

May God bless Dr. Conner and his research dept. and bestow upon them many grants, and may he figure this iron thing out for us all!!!
Hope your Mom is doing OK, and that the docs are figuring out her iron issues. This is w-a-a-ay too complex for me, but I know there's something here.
AC

[dignan]

Here's a new study from Zamboni et al...


BACKGROUND: the extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have never been investigated.

METHODS: Sixty-five patients affected by CDMS, and 235 controls composed, respectively, of healthy subjects, healthy subjects older than CDMS patients, patients affected by other neurological diseases, and older controls not affected by neurological diseases but scheduled for venography (HAV-C), blindly underwent a combined transcranial and extracranial Color-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. According to the TCCSECD screening, patients and HAV-C further underwent selective venography of the azygous and jugular venous system with venous pressure measurement.

RESULTS: CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29-65, p<0.0001). Subsequently, venography demonstrated in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments; it configures a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of distribution of stenosis and substitute circle. Moreover, relapsing-remitting and secondary progressive courses were associated to CCSVI patterns significantly different from those of primary progressive (p<0.0001). Finally, the pressure gradient measured across the venous stenosies was slightly but significantly higher.

CONCLUSION: CDMS is strongly associated with CCSVI, a picture never been described so far, characterized by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.

for full article:
http://jnnp.bmj.com/cgi/rapidpdf/jnnp.2008.157164v1

[Terry]

I think this is the most alarming thing I've read for some time. I read this last night and went to bed worrying about my cerebral blood flow- awoke woryring about my blood flow. Yech!
Can't wait for Cheer and others to read this.

The million dollar question-

Are venous stenoses the cause or products of MS?

Finally, an additional possibility could be related to the side effects of MS drugs on the venous wall although these have never been reported.

I'm curious about that. Too bad they didn't break the results out showing meds/ no meds.

I am waiting for the day that someone finds the "bottom line". Are we getting closer? I sure hope so.

Terry

Terry

[cheerleader]

Thanks so much for turning us on to Zamboni, Dignan. His work is fascinating. Zamboni's recent study found in MS that a "stenosing lesion" rather than valvular incompetence, creates a reflux situation. ( A stenosing lesion is different than a demyelention...stenosis comes from the Greek meaning "narrowing" of the blood vessels.) This venous cycle would eventually permit a break in the blood brain barrier-

In this study we described the association between MS and the altered modality of venous return determined by extracranial multiple venous strictures. In our controls, venography quite resembled the normal imaging of extracranial cerebrospinal veins. 25 The hampered cerebrospinal venous drainage in patients with MS determines a complex haemodynamic picture defined as CCSVI. It is characterized by multiple substitute circles, with a very high incidence of reflux in both intracranial and extracranial venous segments and loss of the postural regulation of cerebral venous outflow.
The mechanism underlying this reflux differs from the reflux caused by
incompetence of the jugular valve. In the latter case, valvular insufficiency tested with Valsalva can be related to a picture of transient global amnesia.14
In our study the reflux occurred in any body position without the need to elicit it by a forced movement, suggesting that it is not an expression of valvular incompetence but rather of a stenosing lesion that cannot be crossed with postural or respiratory mechanisms, thereby becoming a long-lasting reverse flow.
Substitute circles are alternative pathways or vicarious venous shunts28 (Fig. 3) that allow for the piping of blood toward available venous segments outside the CNS. In accordance with the pattern of obstruction, both the intracranial and the intrarachidian veins can also become substitute circles; they permit redirection of the deviated flow, preventing intracranial hypertension. However, over time they become overloaded because they carry two different flows, their own draining flow and the shunted flow (Fig. 3).

Doppler scans are allowing doctors to see blood flow. They were just used in an endothelial study, and Zamboni's team is learning amazing things regarding the "reverse flow" created by obstruction. His team could see different types of chronic cerebrospinal venous insufficiency (CCVI) depending on course of MS- PPMSers had vascular obstruction of the azygous vein in the back (runs along the spine in the lumbar area)

We also observed that the PP course was related to a CCSVI pattern significantly different as compared to RR and SP, suggesting that the location of venous obstruction plays a key role in determining the clinical course. For instance, PP course, characterized by a slowly progressive syndrome with spastic paraparesis and MRI demonstration of MS plaques in the spinal cord, 20,30-32 was significantly associated to obstruction at several levels of the azygous vein and of the lumbar plexuses (type D pattern, Fig. 3, Table III). In
this situation venous blood of the spinal cord can be drained only in an
upward direction, and is shunted toward the venous plexuses inside the spine (Fig. 3, 4), contributing to explain the correlation between type D and spinal cord involvement in PP patients.

Zamboni believes the venous obstructions are most likely causative of MS, rather than a result...causing damage throughout the venous system, down to the liver, creating the hallmarks of MS...inflammation and lesions.

Moreover, the absence of Doppler and venographic features of CCSVI in controls suggests that venous obstructions may be causative of MS rather than a coincidental finding.

Interestingly, similar venous stenoses considered to be congenital
malformations have been described in other human diseases, i.e.,
membranous obstruction of the inferior vena cava and a minor group of
chronic venous diseases of the lower limbs.27-28 Such venous obstruction
brings about an insufficient venous drainage, respectively at the level of the liver and of the cutaneous tissue, subsequently causing inflammation,
sclerosis, and degenerative lesions.24-25,36

A suggested protocol for MS patients which would replace MRI with doppler screening- since Zamboni believes that MRI only shows the resultant damage of MS, rather than the cause. Doppler screening would be cheaper, and would explain why those with PPMS, who no longer show signs of inflammation, continue to progress. Because Zamboni believes (as do I) that MS is not caused by inflammation or an autoimmune response, but rather a break down of the circulatory system.

Finally, on the bases of our study we could propose the introduction of the ECD-TCCS protocol when a patient presents the first acute episode of demyelinating origin, mostly involving the optic nerve, the so-called clinically isolated syndrome (CIS).
Currently, only longitudinal clinical and MRI observation in time and space is capable to establish the possible conversion of a CIS into CDMS.20

Terry...don't lose sleep over your blood vessels. But please, stop smoking and follow a good heart healthy diet. I only say this cause I care As far as MS meds, yeah...chemo is tough on the blood vessels. Not sure how copax or interferons treat the vascular system. But if pharma is only looking at the results of venous drainage and not the cause of MS...we gotta look after each other...
AC

[Terry]

Lol, Cheer. I know my smoking gets your goat.

I quit smoking once in the 90's. During the quitting, I could not make sense of what I saw. The pictures I saw with my eyes would not translate to my brain. I quit again in 2000. Shortly thereafter, I began to have the bend in my vision. Since diagnosis, I've wondered if I shocked my system too badly. Started smoking again in 2007, a year after diagnosis (for reaons unrelated to MS). I have to admit that I am AFRAID to stop again. If I do, it will have to be a VERY slow taper. Just trying to maintain, that's all.
As far as my diet, I was crazy strict at first. I have relaxed on that very much. After over a decade on a low carb diet (mostly) before diagnosis, after diagnosis I swung toward organics and low fat. Now, about all I can say is I try to stay away from nitrates, artificial sweetners, overly processed foods, and milk that is not organic.
Zamoboni didn't actually say that there was leakage of the blood into the brain, did he? Would he have been able to see that? I spent the overnight Thursday night with my daughter-in-law at the ER. Probably she has a seroma after a c section. A seroma is caused by leaking blood vessels. They do not leak blood, but a clear fluid. I wonder what is in that fluid. I had no idea that a vessel could leak anything but blood. Seems that everything is a learning exerience for me these days.
Have aura from migraine now. Must quit trying to see the computer screen.
Terry

[cheerleader]

Lol, Cheer. I know my smoking gets your goat.

sorry, Terry. I'm like Oprah- - telling everyone else how to be healthy while I eat an entire pecan pie-with whipped cream. Next time I do that, just say...."step away from the chocolate, cheer." Sounds like smoking has affected your system, with the vision and migraine stuff. Hope you feel better.

Zamoboni didn't actually say that there was leakage of the blood into the brain, did he?

No, he saw "venous obstructions" and "stenosing lesions" and narrowed arteries in every single MS patient he dopplered (is that a verb?) I'm afraid to throw this out there...but that sounds like blood clots to me.

I spent the overnight Thursday night with my daughter-in-law at the ER. Probably she has a seroma after a c section. A seroma is caused by leaking blood vessels. They do not leak blood, but a clear fluid. I wonder what is in that fluid. I had no idea that a vessel could leak anything but blood.

So sorry for your daughter in law. Never heard about seromas, but it looks like they can happen after surgery if serous fluid (blood serum, which is clear) is excreted, and a pocket of liquid forms. Hope she's doing better.