The pattern of joint pain due to iron overload

Hi,

It's been quite long since I last posted here... I was distracted by looking for different strange syndromes that I may have, but still did not find the final answer. And in the end it may all come down to some kind of hemopathy (I am not even sure if I have thalassemia minor although it was confirmed by electrophoresis but... there are doubts).

Now, I've been qualified for whole genome sequencing (given the latest findings - I qualify) but before they perform the sequencing and analysis, my condition may get much worse... as it is getting much worse right now... I don't know if I survive...

My problems include (and this is very approximate list):
1. Muscle pain and weakness (recently clearly confirmed by an EMG test, see below)
2. Nerve inflammation, damage and paresthesias (recently clearly confirmed by an EMG test, see below)
3. Some kind of hemopathy (maybe thal minor, but possibly sideroblastic anemia, see below)
4. Tendon inflammation, ie. tendonitis (and joint inflammation to some degree)
5. Many other resultant effects of the above...

So recently points 4 and 2 are making my life really miserable... I need to take care of them really fast.
I came to conclusion (also based on EMG test result) that nerve inflammation is a straight consequence of tendon inflammation. Inflammation also includes joints (in the places where tendons meet the joints).
The first tendons affected were tendons just above the elbows and just above the knees, then wrist (joint), then the inflammation started developing on both sides of spine (thus nerve roots were inflamed and that is what EMG showed), the tendons just below shoulders. Basically from the very beginning also my knuckles (so-called metacarpophalangeal joints) were inflamed, especially thumbs.

The funny thing about tendonitis is that it is difficult to find a cause of it. Basically all of the inflammatory disorders concern joints... and I have very well defined points of inflammation in tendons...

Sidenote: gout was excluded, so any other kind of arthritis at a very renowned facility, including the so-called seronegative rheumatoid arthrytis and ankylosing spondylitis (these were actually considered but excluded at this facility).

And now recently I found this article:
http://ard.bmj.com/content/41/1/97.full.pdf
Sideroblastic anaemia with iron overload presenting as an arthropathy

We report on 2 patients with sideroblastic anaemia and secondary iron overload whose presenting symptom was an arthropathy of small and large joints. One patient had marked spinal symptoms which were severe enough to suggest ankylosing spondylitis, and the pattern of arthritis in the other resembled seronegative rheumatoid arthritis. We believe these to be the rirst cases described of an arthropathy associated with iron overload secondary to sederoblastic anaemia.

Wow! Sounds like my symptoms.
The suscpected order of events in my case is:
- impaired production of red cells (thal minor or sideroblastic anaemia), ie. inability to incorporate iron to hemoglobin
- iron aboundance (no clear or standard signs of iron overload - ferritin was in normal range, but 130 which is suspicious because it should (so they say) be below 100 in normal people, also Ferriscan was performed - completely within normal range), but transferrin saturation was extremely high (like 90% as far as I remember), blood iron was twice over the normal range...
Here, they say that people may have low ferritin and high saturation and thus get iron overload:
http://www.americanhs.org/faq.htm

A percent of saturation of more than 40% (in African Americans) and 45-50% (in Caucasians) and/or a serum ferritin of more than 150 are considered suspicious for iron overload/hemochromatosis. It is important to note that in some patients, the percent of saturation can be quite high while the ferritin rather low (this is often the case in children or young adults in their 20's)

But bear in mind that I only claim that in my case iron only precpitates in joints, so it is not iron overload per se...
- (speculation) iron precipitates in tendons and joints
- tendons and joints inflammation
- nerve inflammation and parethesias

Funny thing... after taking vitamin B6 (or rather P-5-P or pyridoxal phosphate in case I may also have something called pyridoxine/pyridoxal responsive anemia) about 3 months ago reticulocytes increased, iron saturation dropped to 25%... so this means something. In case of such anemias blood letting is recommended but basically no doctor will ever order that before I get a final diagnosis and I can't donate blood (they ask me: do you suffer from any chronic disease, I reply: where do I start...   ).
Instead, I started taking IP-6 on a very frequent basis - supposedly it has the ability to make you iron deprived in just 3 months but these are rather unconfirmed claims... I intend to reach ferritin equal 10...

QUESTIONS!!!
If you managed to read that far, thank you for that.
Now it's time to answer some questions, if you will...

1. Can a person with confirmed iron overload (sideroblastic anemia would be ideal, see below, major thal will have to do) tell me what is that pattern of joint pain in case of iron overload? Is it any similar to the description of my pains (tendons, etc.)?

Any ideas about iron overload in joints in general?

2. Does anyone have any ideaa about the possible mechanism of the iron ending up in my joints and not anywhere else?

I know it's a long shot because probably nobody has a similar problem, and the research papers on this kind of problem are scarce as hell.
If it wasn't for that paper "Sideroblastic anaemia with iron overload presenting as an arthropathy" I'd still be kept in the dark.

The problem with sideroblastic anemia is that it is supposed to be a little different than other anemias. It causes precipitation of iron in erythroblasts in small clumps of hemosiderin (these are not present in thal minor) but in order to confirm that I would have to have my bone marrow tested (not possible in foreseeable future as the hematologist is convinced I have beta thal minor and that's it, no further diagnostic procedures required).
It causes high iron saturation, and that's what I had, so what I think is that in favourable circumstances this iron would be inclined to precipitate in joints, these favourable circumstances being low blood flow in joints (and tendons), lower temperature than the rest of the body... and possibly other factors.

3. So this actually begs another question: why iron has a tendency to accumulate in joints (beyond the reasons above)?

Regards,
Bigg

Further developments...

I recently received 23andme results.
I did not notice that at first (there are no health results presented by 23andme, you have to rely on your own analysis and third-party tools) but today I found that I have this (homozygotic) mutation:

http://www.snpedia.com/index.php/Rs34502690%28D;D%29

This is not an ordinary mutation but still results in Beta-thalassemia minor. This is the paper that describes this mutation:

Characterization of beta-thalassemia mutations among the Japanese.

Abstract

Characterization of beta-thalassemia mutations were attempted for 29 Japanese families clinically diagnosed as having beta-thalassemia. Following the identification of a mutation by cloning and sequencing, all families were screened for this particular mutation, using biotinylated allele-specific oligonucleotide probes. Seven different mutations were detected in 17 families: Six families had the frameshift mutation at codons 41/42, resulting from a 4 nucleotide deletion (TTCTTT----TT); four had the deletion at codons 127/128 (CAGGCT----CCT); and three had the TATA box mutation at nucleotide -31 (A----G). Four additional families had mutations at codon 24 (GGT----GGA), codon 26 (GAG----AAG), IVS-II-654 (C----T) and codon 110 (GTG----CCG), respectively. The newly discovered deletion mutation at codons 127/128, and mutations at nucleotide -31, and at codon 110 are peculiar to Japanese, and have not been found in any other ethnic group. The haplotypes of the beta-globin gene cluster were also determined. Some of the haplotypes and beta-thalassemia mutations are identical to those reported in the Chinese population. However, it is noteworthy that nearly half of the beta-thalassemia mutations were unique to Japanese.

And until now it was supposed to be restricted to Japanese, but not anymore, because I am caucasian.

The real question thus becomes: how do I find if there is iron overload in the joints?
If there is no overload in liver... yes, it sounds crazy, but similarly crazy is transferrin saturation level of 90% that I had (people with iron overload (HH for example) usually have 45-55%, as I read different confessions)... That would mean that iron distribution dynamics may be completely different from normal...
If I don't find iron overload in the joints and I don't convince the hematologist to prescribe phlebotomy, then what do I do? The only answer is to perform phlebotomy myself... Afterall it should not be that dangerous, given that it is possible for me to order blood tests myself and thus control the appropriate blood parameters (ie. ferritin, hematocrit). But there is always possibility of other complications like clots...

Bigg

Bigg,

Do you have the name of the specific deletion? There are 4 different ones at codons 127/128. It would help to know the specific deletion.
How long have you been using IP6? Has there been any improvement?
Do you have the hemoglobin electrophoresis results? I'd like to see if anything stands out as unusual.

Do you have the name of the specific deletion? There are 4 different ones at codons 127/128. It would help to know the specific deletion.
How long have you been using IP6? Has there been any improvement?
Do you have the hemoglobin electrophoresis results? I'd like to see if anything stands out as unusual.

Oh, boy - it's kind of difficult to answer these question, but they are really good questions that made me think and reach some conclusions. I think these conclusions are of greatest importance for other people. Hopefully I will not forget to mention all of them.

Do you have the name of the specific deletion? There are 4 different ones at codons 127/128. It would help to know the specific deletion.

I only know that it's this mutation:
http://www.snpedia.com/index.php/Rs34502690%28D;D%29
and nothing else... this should provide info what kind of mutation it is, shouldn't it? If not, could you provide some info what these different deletions are? Maybe I will be able figure something out.
This is the actual part of the genome file:

rs35834416   11   5246881   AA
rs63750860   11   5246884   DD
rs34502690   11   5246887   DD (disease causing mutation)
rs34139813   11   5246887   CC
rs34843844   11   5246893   II

But take the above rs63750860...
This:
http://www.snpedia.com/index.php/Rs63750860
kind of also shows that this (ie. deletion or DD) is not normal...
Normal is (GCTG;GCTG)

Most important for other people: 23andme tests for many mutatation (or SNPs) in HBB gene and it can still be easily read by Promethease project (despite FDA causing 23andme to stop releasing health reports). But it is still difficult to interpret, and I found this particular mutation only after a month after having received the report, because you can read the description (and I know I read it) but it still does not mean too much to you... only after I search for thalassemia, I found it.
So it may be a viable research tool for thalassemia, if one needs confirmation. And relatively cheap tool... Me for example - I could have ordered the HBB gene sequencing (only one gene; not all people are able to do that by themselves, in the US for example) for 250 dollars or I could have ordered 23 and me test of SNPs for 99 dollars. Moreover, looks like there are so many SNPs for HBB gene tested, that they probably cover many many possible mutations, so basically you won't get any additional info from HBB gene sequencing, unless you have a novel mutation...

My mutation is a very strange mutation and a very strange case, because from the inheritance pattern which in this case is autosomal recessive it can be seen that I am Affected (see here: http://en.wikipedia.org/wiki/File:Autorecessive.svg).
Or am I missing something?
This mutation must be very very rare (so the carriers are very rare) so it is almost impossible for my mother and father to be carriers at once (because they do not have any symptoms). So this may imply that they are related (and they are not, they come from two different parts of the country) or I may have the same copy of one allel from the same parent (I don't know if I am making myself clear... that would be a genetic disturbance but I do not know the name of it or if I am making any sense now). If such (xeroxed from one allel from one parent) genes are common in my genome, then it would explain a lot of diffferent ailments... I will have to try to figure this out.

It is difficult to analyse the genome file by hand.
Take for example the above SNP:
http://www.snpedia.com/index.php/Rs35834416
It says that (T;T) is normal and I have AA. But I don't have any mutation here, it's all because of naming convention - TT becomes AA on the complementary DNA strand.
Here is the explanation:
https://customercare.23andme.com/entries/21272593-which-dna-strand-does-23andme-report-for-snp-genotypes

I have mutation rs34502690(D;D) which means that I am homozygotic. This would normally (ie. as in the case of other more common mutations) mean Beta Thalassemia Major. But I have Thalassemia Minor, ie. I do not require transfusions.

If homozygotic mutation causes so (relatively) mild symptoms then it means that heterozygotic mutation will not cause any symptoms at all (also see the explanation below marked with ##). That would explain why none of my parents is affected by this although they are carriers for sure ie. have this same but heterozygotic mutation.

Until now I wasn't quite sure if I have some kind of thalassemia or any other kind of blood disorders or maybe something like vit. B6 processing inadequacy (lack of vit. B6 metabolites (ie. pyridoxal phosphate) also causes similar symptoms, microcytic anemia etc. and my anemia reacts to pyridoxal phosphate supplementation although not that well). I am very well aware how these rare mutations and lab tests can be misleading, and in my case things just didn't add up (now they do).


## Looks like this mutation causes problems with hemoglobin assembly. This means that there is a lot of iron floating around because hemoglobin is not assembled. But in the case of heterozygotic gene mutation (as my parents or carriers would have) this iron is picked up by other normal assemblies of normal hemoglobin (made based on the "healthy" allel of the gene). So the iron is normally utilized.

But in my case iron is abundant but can't be utilized so the body might think: oops, no iron available. Thats why transferrin level is so high and transferrin was so saturated... Fortunately it looks like vitamin therapy that I employed is working, ie. now the saturation level is 25%. Did iron hurt me if there was only transferrin elevated, not ferritin? It might have...

Does Ip-6 help? Yes it does, and how. But it has rather something to do with this mode action: it inhibits http://en.wikipedia.org/wiki/Phospholipase_A2
So it may be used to treat some inflammatory problems, and in this respect it works for me, although it may also work by chelating too much iron that is still floating around.

The worst problem is that one pint of donated blood would let me get rid of so much iron that IP-6 is able to chelate in... a very long time. So it's a bummer that I can't donate blood just like that...

Regarding electrophoresis results, I already provided them quite long ago:
http://www.thalassemiapatientsandfriends.com/index.php/topic,1701.0/highlight,transferrin.html

Yup, electrophoresis results are abnormal...

Uniparental disomy... thats what I meant by saying "xeroxed genes from one allel from one parent"...

http://en.wikipedia.org/wiki/Uniparental_disomy

Looks like I may have it...

Again, take a look at the fragment of the genome:
rs35834416   11   5246881   AA
rs63750860   11   5246884   DD (probably very very rare deletion)
rs34502690   11   5246887   DD (probably very very rare deletion)
rs34139813   11   5246887   CC
rs34843844   11   5246893   II

So if I have two very rare deletions, this may only mean uniparental disomy...

hi! i came across this post because i was looking for information about the deletion i have. i just found out about it 2 days ago from 23 and me, so there's still a lot i don't know yet.

but i felt i should reach out to you Bigg because my results are exactly the same as yours & i'm also polish, which i noticed you mentioned in the other post you linked. given that andy said there are 4 different deletions at codons 127/128, i've started to wonder if maybe we have the same one & maybe it's different from that found in japanese patients.

also, you described that your results looked like one parent's gene had been xeroxed. i observed the same thing… every base, insertion, & deletion is identical for both strands of the HBB SNPs tested & i thought that seemed odd.

i'm not exactly sure what all this means yet but i've been a patient for 13 years because i started to feel bad when i was 18 & even though they found things along the way & tried to address them, i've never really gotten better. maybe this is part of the reason why so i'm curious to see what happens next.

lastly, andy, if you see this post, i was wondering if you could give us what ever information you have about the 4 different deletions at codons 127/128. i would really appreciate that!

Joints are really troubling, too much pain, inflammation....can't even sleep.... Is it iron really??

Rashmi,

Various things can cause joint pain and iron is one of these. Don't skip chelation, especially right after transfusion. That is when the amount of free iron in the blood is highest. Kelfer can also cause joint pain. It may also be a side effect of other drugs like bone drugs. Are you making sure you're getting enough vitamin D?

Bigg and Mara, I need to look these posts over more thoroughly, but I have a fear that you both may be getting misinformation in these reports as to the specific mutations you carry.

Mara, would you have the results of your hemoglobin electrophoresis test?

This is the Japanese variant. There is a very short history of recording thalassemia variants in the Polish population, so it could be that this is not unique to Japanese or that it is a similar looking variant, but one that has not yet been cataloged.

http://globin.bx.psu.edu/cgi-bin/hbvar/query_vars3?mode=output&display_format=page&i=962

I wander if such thing is happening with me 
I have taken  over the counter iron between  June 2013 through October 2013 unaware of being alpha thal minor,and also has been prescribed by my doctor. They didn't check my blood again until I went back complaining of abdominal pains . They check this time and noticed that my " anemia" was worse and prescribed iron gluconate after one month in the iron prescribed pills they doubled my intake.the abdominal pain came and went as often as once a month. February 2014 was my worst " anemic exam" and my PCP send me to the hematologist. The hematologist prescribed 4 pills of iron gluconated daily. I took it until May 1 2014. Since End of January I was noticing dizziness, fatigue, internal abdominal pain often and often. Difficulty finding words ,forgetful a lot, and March the joint pain started at first on my right knee, and long bones it reached a point that I was completely worthless. I was not able to work,homeschool my child,clean my house. And at that point I was still being tested by an hematologist that already had Upper GI  and colonoscopy done and a CT scan done. So may first I went to my app thinking that I was going to received a diagnostic of Leukemia or MDS syndrome . For myself I had not though I could havee thallassemia cause my iron serum and ferritin were always in normal ranges. I was not happy at all to received the news I had thallassemia and just that day the doctor asked me to stop the iron and didn't really check my iron or care about the pain I was going through. I'm just writing about it now ,because after 19 days without iron I still suffering the same pain. My joins are really sore even not taking iron anymore and with a diet changed , my doctor still telling that my iron levels are fine but I have lost couple days of work again. I'm thinking in print everything you have shared and try to make my doctor ask for flobotomy .

Just to have an idea in the last six months or 180 days I took over 400 pills of iron that I had the empt bottles to show. I just don't remember if I dispose away any. This is just the iron gluconate .

I'm thal minor with hundreds of issues since years, especially disabling fatigue, daily pain/migraines, sleep disorder, etc.  I'm looking into fibromyalgia and adrenal fatigue - wondering if anyone has read about it? My ferritin has always been too low 10-20, but taking iron causes severe hormonal problems. so i go with a multivit with very low iron.

Hi Prets, do you know your vitamin D level? Deficiency is usually found in those with fibromyalgia.