BID theory and ferritin levels

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Frunobulax
Posts: 153
Joined: Mon Jun 02, 2014 7:41 pm

BID theory and ferritin levels

Postby Frunobulax » Mon Jul 08, 2019 10:59 am

I'm sorry for spamming this forum here a bit, but I feel like I'm getting closer and closer to discovering a few things about this wretched RLS...

About BID (brain iron deficiency) and RLS. I understand that many patients have low iron levels in the brain, yet high ferritin levels. I also know that high ferritin levels seem to correlate with inflammation. What's the relation here?

To be more precise, there has been some recent research that shows high ferritin levels in certain population groups (Beth linked one article in viewtopic.php?f=5&t=10455, whose conclusions I find highly suspicious). It seems that whenever there is some inflammation, oxidative stress and/or or an auto immune response, ferritin levels rise (https://www.ncbi.nlm.nih.gov/pubmed/24549403). However, high ferritin levels will lead to reduced iron uptake through digestion (see the IRLS study group paper https://www.sciencedirect.com/science/a ... via%3Dihub, hepcidin). But what's going on here? That sounds like a fairly fatal vicious circle: Iron deficiency leads to inflammation/autoimmune reactions, inflammation leads to high ferritin levels, high ferritin levels will block the absorption of iron. But what am I missing here? How can we have high ferritin levels if our iron stores are depleted? Could it be that we got it wrong, the iron is somehow used up by the inflammation and a lower percentage of the iron uptake goes to the brain? Something does not make sense here :)

In any case Ferritin appears to be not a reliable marker for our iron stores, and I wonder if we're making a big mistake by looking too much at the ferritin levels and not enough at the other iron markers (transferrin saturation for example).

stjohnh
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Location: Palo Alto, California

Re: BID theory and ferritin levels

Postby stjohnh » Mon Jul 08, 2019 2:13 pm

Frunobulax wrote: I understand that many patients have low iron levels in the brain, yet high ferritin levels. ...


In one of the webinars on the RLS foundation site (I'm pretty sure it was the one by Dr Earley on iron), he stated ALL patients with RLS have low brain iron. This includes RLS patients with hemochromatosis (genetic iron overload, most of those people have a blood ferritin of over 1000). The only possible exception that I know of may be RLS patients with chronic kidney disease on dialysis. I'm not sure if their brains have been tested for low iron levels, in any case, their metabolism is SEVERELY abnormal due to kidney failure.
Frunobulax wrote: I also know that high ferritin levels seem to correlate with inflammation. What's the relation here?

To be more precise, there has been some recent research that shows high ferritin levels in certain population groups (Beth linked one article in viewtopic.php?f=5&t=10455, whose conclusions I find highly suspicious). It seems that whenever there is some inflammation, oxidative stress and/or or an auto immune response, ferritin levels rise (https://www.ncbi.nlm.nih.gov/pubmed/24549403). However, high ferritin levels will lead to reduced iron uptake through digestion (see the IRLS study group paper https://www.sciencedirect.com/science/a ... via%3Dihub, hepcidin). But what's going on here? That sounds like a fairly fatal vicious circle: Iron deficiency leads to inflammation/autoimmune reactions, inflammation leads to high ferritin levels, high ferritin levels will block the absorption of iron. But what am I missing here? How can we have high ferritin levels if our iron stores are depleted? Could it be that we got it wrong, the iron is somehow used up by the inflammation and a lower percentage of the iron uptake goes to the brain? Something does not make sense here :) ...


Ferritin is a storage protein that is in all tissues, AND in the blood. The blood level (what is ordinarily measured) correlates well with the amount of iron stored in the bone marrow. It does NOT correlate well with iron stored elsewhere, especially the other major iron storage organ, the liver. The total amount of iron represented by the ferritin in the blood is only a tiny amount compared to the total iron stored in the body, so having a high ferritin along with total body low iron is not contradictory.

I think that the hepcidin/ferritin-intestinal iron uptake balance has not been fully worked out. People with high ferritins due to inflammation are very common and only some of those have iron deficiency anemia, so they are absorbing significant iron from their intestines. I'm not sure how much the ferritin level vs hepcidin response has been studied in those people. Maybe there are different sub-classes of ferritin (like there are subclasses of cholesterol) and only some of those affect the hepcidin levels.
Frunobulax wrote:..In any case Ferritin appears to be not a reliable marker for our iron stores, and I wonder if we're making a big mistake by looking too much at the ferritin levels and not enough at the other iron markers (transferrin saturation for example).


YES YES YES!! You are getting it. Unfortunately many on this forum still don't get this, perpetrated no doubt by the fact that most doctors ALSO don't get this, and their response to their RLS patients who say "what about iron doctor?" is "your ferritin is normal, don't worry about iron." BIG problem in education of patients and doctors.

This is discussed somewhat in the consensus paper. If you read carefully you will see they hedge on the ferritin they consider OK for IV iron. They say "don't give IV iron if the ferritin is over 300" yet their official recommendation is only give initial IV Iron if ferritin is below 100. They discuss this somewhat, but to me it appears clear that they consider IV iron OK if the ferritin is up to 300, as long as the %transferrin saturation is less than 45%. But they can't give this as an official recommendation due to not enough clinical studies supporting this. We REALLY need better tests of both brain iron and total body stores of iron.
Blessings,
Holland

Frunobulax
Posts: 153
Joined: Mon Jun 02, 2014 7:41 pm

Re: BID theory and ferritin levels

Postby Frunobulax » Mon Jul 08, 2019 7:16 pm

stjohnh wrote:Ferritin is a storage protein that is in all tissues, AND in the blood. The blood level (what is ordinarily measured) correlates well with the amount of iron stored in the bone marrow. It does NOT correlate well with iron stored elsewhere, especially the other major iron storage organ, the liver. The total amount of iron represented by the ferritin in the blood is only a tiny amount compared to the total iron stored in the body, so having a high ferritin along with total body low iron is not contradictory.

I think that the hepcidin/ferritin-intestinal iron uptake balance has not been fully worked out. People with high ferritins due to inflammation are very common and only some of those have iron deficiency anemia, so they are absorbing significant iron from their intestines. I'm not sure how much the ferritin level vs hepcidin response has been studied in those people. Maybe there are different sub-classes of ferritin (like there are subclasses of cholesterol) and only some of those affect the hepcidin levels.


Makes sense :-) So we should have responders to oral iron even if the ferritin is high, is that the correct conclusion? That would be the case if hepcidin is not dependent on serum ferritin but on ferritin levels in other areas where ferritin does not go up from inflammation. Well, we can hope :)

Frunobulax wrote:..In any case Ferritin appears to be not a reliable marker for our iron stores, and I wonder if we're making a big mistake by looking too much at the ferritin levels and not enough at the other iron markers (transferrin saturation for example).


YES YES YES!! You are getting it. Unfortunately many on this forum still don't get this, perpetrated no doubt by the fact that most doctors ALSO don't get this, and their response to their RLS patients who say "what about iron doctor?" is "your ferritin is normal, don't worry about iron." BIG problem in education of patients and doctors.

This is discussed somewhat in the consensus paper. If you read carefully you will see they hedge on the ferritin they consider OK for IV iron. They say "don't give IV iron if the ferritin is over 300" yet their official recommendation is only give initial IV Iron if ferritin is below 100. They discuss this somewhat, but to me it appears clear that they consider IV iron OK if the ferritin is up to 300, as long as the %transferrin saturation is less than 45%. But they can't give this as an official recommendation due to not enough clinical studies supporting this. We REALLY need better tests of both brain iron and total body stores of iron.[/quote]

Yes, I've been talking about transferrin% ever since I first read that paper. I noticed that discrepancy and scratched my head a bit, it kinda stands out as an inconsistency in an otherwise well written paper.

But I guess Iron is something that we haven't really grasped. I figure that Transferrin% is probably not a reliable marker for iron stores either, and anemia is clearly not the only symptom of low iron stores. Obviously low transferrin% or low ferritin is a marker of an iron deficiency, but how do we spot the patients that have normal transferrin% and ferritin but still have iron deficiency?

Footnote.
This is fairly crucual for me because I'm suffering from ME and RLS both... Iron has a pivotal role in energy management, as it is required to manufacture carnitine (among many other uses) which is in turn required to gain energy from fat. Low iron is very bad news for people with myalgic encephalomyelitis/chronic fatigue as nitrosative stress blocks the citrate cycle for CFS/ME patients, and carnitine/iron deficiency will block the fat burning, hence there is nothing left to manufacture energy (except possibly the processes that create even more nitrogen monoxide, in turn elevating the nitrosative stress even more).

CFS/ME is fairly common among RLS patients of course.

For me the onset of chronic fatigue came after a phase where I had to stop pramipexole cold turkey and was going through several other treatments (idiot doctors tried to treat me with Gabaopentin and Lyrica after severe augmentation, not even Gabapentin enacarbil). There wasn't a direct connection to iron as far as I can tell, and no change in my RLS, possibly as a result of an EBV infection. That was 5 years ago... But I've been recently experimenting with high doses of Carnitine and Glutamine, both seem to help me significantly with my fatigue, but my RLS symptoms are getting worse instead of getting better. Very strange.

stjohnh
Posts: 850
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Location: Palo Alto, California

Re: BID theory and ferritin levels

Postby stjohnh » Mon Jul 08, 2019 8:25 pm

Frunobulax wrote:...Makes sense :-) So we should have responders to oral iron even if the ferritin is high, is that the correct conclusion? ...


Well, sort of. The problem is that even with a ferritin of only 100 in the absence of inflammation, the hepcidin levels respond, drastically limiting the uptake of iron from the intestine. For most people with RLS without extra inflammation artificially boosting the ferritin, the ferritin needs to be higher than can be achieved using oral iron. So, yes, there are responders to oral iron, but not many, and especially few who already have a ferritin of over 100.
Blessings,
Holland

Frunobulax
Posts: 153
Joined: Mon Jun 02, 2014 7:41 pm

Re: BID theory and ferritin levels

Postby Frunobulax » Fri Jul 12, 2019 11:18 am

stjohnh wrote:
Frunobulax wrote:...Makes sense :-) So we should have responders to oral iron even if the ferritin is high, is that the correct conclusion? ...


Well, sort of. The problem is that even with a ferritin of only 100 in the absence of inflammation, the hepcidin levels respond, drastically limiting the uptake of iron from the intestine. For most people with RLS without extra inflammation artificially boosting the ferritin, the ferritin needs to be higher than can be achieved using oral iron. So, yes, there are responders to oral iron, but not many, and especially few who already have a ferritin of over 100.


I'm a bit undecided about the subject of inflammation, silent inflammation and health risks in general. I have read studies that obese people tend to have higher ferritin, and so do other patients with chronic but not life threatening conditions like diabetes or gout, despite having no significantly elevated inflammation markers like CRP. It wouldn't surprise me at all if there was a fairly large subgroup of patients with high ferritin but generally low iron.

Case in point, even though it's sample size = 1: During the last half year I ate low carb, added more iron to my supplements (65mg daily instead of 14mg) and cut PPIs, therefore having more stomach acid and in theory a better iron uptake. (I always take 1g vitamin C with the iron.) I was able to reduce my evening dose of Oxycodone from 20mg to 15mg and sometimes 10mg at the end of that period, until I stopped taking the iron supplements (basically because I was in a clinic that suggested that I stop, and reading about the hepcidin and thinking "with Ferritin around 200, maybe these iron supplements create only expensive urine"). 2 months after going back to 14mg iron a day I'm back at 20mg Oxycodone in the evening... Many of my bloodwork looks a lot better now, except - drum roll - the ferritin, that dropped from 225 to 180 in that period.
I do have CFS which is considered an autoimmune disease by researchers, and I do feel better than half a year ago, so my personal experience would support that (a) oral iron helped me despite having high ferritin, an (b) doing something that helps with my CFS resulted lower ferritin levels. I also do believe that leaky gut is an issue that may cause an autoimmune reaction, and I got that diagnosis too. (Although I don't believe that leaky gut is the source of all problems as some people claim. But I do think it's a piece of the puzzle.)

Of course, we all know that RLS is a b*tch so all this could come from other effects. I would have loved to monitor my ferritin levels a bit more, but I finally managed to obtain an injectafer IV (yay!) so there is an external influence influencing my ferritin... I will go back to 65mg iron a day or more if I my digestion cooperates, and am very curious to see what my iron levels are in 2 months and 4 months.

stjohnh
Posts: 850
Joined: Sun Feb 14, 2016 3:13 pm
Location: Palo Alto, California

Re: BID theory and ferritin levels

Postby stjohnh » Fri Jul 12, 2019 1:09 pm

Frunobulax wrote:... It wouldn't surprise me at all if there was a fairly large subgroup of patients with high ferritin but generally low iron...


I think we need to get away from the idea of "generally low iron" and realize that, except in very limited circumstances, that for proper functioning different organs need different levels of iron. Much better to speak of low brain iron (BID), or low bone marrow iron (iron deficiency anemia), etc. But I agree with the idea that there are probably lots of people with ferritins above 100 that have low brain iron and could benefit from IV iron infusions, but can't get them because our ability to test for iron levels at the organ level is close to non-existent.
Blessings,
Holland

fuz_mind
Posts: 79
Joined: Sun Apr 23, 2017 4:27 pm

Re: BID theory and ferritin levels

Postby fuz_mind » Tue Jul 16, 2019 3:22 pm

stjohnh wrote:
Frunobulax wrote:... It wouldn't surprise me at all if there was a fairly large subgroup of patients with high ferritin but generally low iron...


I think we need to get away from the idea of "generally low iron" and realize that, except in very limited circumstances, that for proper functioning different organs need different levels of iron. Much better to speak of low brain iron (BID), or low bone marrow iron (iron deficiency anemia), etc. But I agree with the idea that there are probably lots of people with ferritins above 100 that have low brain iron and could benefit from IV iron infusions, but can't get them because our ability to test for iron levels at the organ level is close to non-existent.



totally agree with the above. my doc doesn't know what to do with me because my ferritin was 114, iron saturation 20%. i managed to arm twist him into a 2nd IV iron 1 year + ago, but I think he got quite a bit of flake from his other neuro colleagues. Interestingly, I have been pain free for a while now, until it resurfaced recently. guess what, my current ferritin is back at 114, iron saturation 20% --> down from 300+ after my 2nd IV.
my doc is refusing another IV iron now because ferritin is above 100 but said I could try oral iron. but he was careful to qualify that he calculated the rate of decline and it was ok, but he ignored my question when I tried to press him if it was a normal rate of decline....

stjohnh
Posts: 850
Joined: Sun Feb 14, 2016 3:13 pm
Location: Palo Alto, California

Re: BID theory and ferritin levels

Postby stjohnh » Tue Jul 16, 2019 7:57 pm

Fuz, see my comment in the "rate of ferritin decline thread." http://bb.rls.org/viewtopic.php?f=20&t=9913&p=99112#p99112
Blessings,
Holland


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