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Where's the iron?

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hemopatient123
hemopatient123

Please see if you can help me figure out my situation. I am not confident that my hemotologist has it right. Here are the facts:

1) 3 weeks ago I had a ferritin of 919, the first time I have ever checked my ferritin. I had a normal TS% of 38%.

2) I also determined then that I am a compound heterozygote for HFE mutations (C282Y/H63D)

3) We performed liver MRI and cardiac MRI (T2) and both have returned results of "no excess iron overload"

4) I've checked for Hepatitis and inflammation, two other causes for a high ferritin. Both labs were negative

5) I started phlebotomy treatment with a hemoglobin of 16.0. Before my 3rd phlebotomy, my hemoglobin was 12.2. After that 3rd phlebotomy, I am definititely now anemic this week.

6) After 2 phlebotomies, my ferritin dropped to 646. Although this is a good drop, still far to go to get below 100 which is ideal for most with hemochromatosis.

Based on all of this, I am confused. Where is all the iron in my body if none is in my liver or heart based on the MRI results? Is my ferritin really high from iron given that my hemoglobin is so low already after only 2-3 phlebotomies? 

Thanks for anyone who has input!

1 like, 11 replies

11 Replies

  • GillianA
    GillianA hemopatient123

    Posted

    Dear Hemopatient123

    It's possible that your ferritin is high because of extra iron in your tissues, but that the extra iron is in tissues other than your liver or heart.  You might want to ask your hemotologist about the possibility of ferroportin loss-of-function (LOF) disease.  I'll do a second post with more details on ferroportin LOF, including references and links to the references. 

    In my case, I *think* I have ferroportin LOF but I don't know for sure because the hematologists where I live have so far declined to do any genetic testing other than for C282Y.  I am C282Y -/-.  Our medical system doesn't do H63D testing, but through private testing, I found out that I am H63D +/+ (which shouldn't cause iron overload). 

    Just in case information on my response to phlebotomy is helpful for you, here's what happened to me:  I started with a ferritin that was 1438 ug/L at its highest and 1382 ug/L just before my first phlebotomy.  I started phlebotomy at weekly intervals.  Because my hemoglobin dropped, after 7 phlebotomies I had to extend the time between phlebotomies to every two weeks, and after 15 phlebotomies, to every 4-5 weeks.  I reached the target ferritin of just under 50 ug/L after 25 plebotomies of 250-350 cc each, for a total of 7.45 L of blood removed.  Even with stretching out the time between phlebotomies, my hemoglobin dropped from its usual 125-130 g/L range to around a 110-120 g/L range while I was having the de-ironing phlebotomies done.  Four months after stopping phlebotomy, my hemoglobin had gone right back up to 128 g/L. 

    MRI was not done until done after my last phlebotomy, when it showed normal iron levels in my heart, liver, spleen, pancreas, and bone marrow.  It was very good to see that the phlebotomy had worked in removing the excess iron, but I wish I had been able to persuade my hematologist to order an MRI earlier on, when the distribution of iron overload in different tissues might have provided a clue to the cause of my iron overload.

    More details on ferroportin loss-of-function disease in the next post  - I hope some of this is helpful for you in discussing your situation with your hematologist!

    • hemopatient123
      hemopatient123 GillianA

      Posted

      Thanks Gillian. This is very helpful. This is also now what I believe I have. Can I ask, how were your symptoms before and after phlebotomies? Any hope for my spine pain or cardiac symptoms?
    • GillianA
      GillianA hemopatient123

      Posted

      My main symptoms are disabling fatigue - I wake up tired and just get more tired as the day goes on.  I need an hour or two nap in the middle of the afternoon.  I can't think properly and have to check and recheck everything I do, and still make mistakes.  This includes regularly messing up really simple stuff such as putting the nuts away in the fridge instead of in the cupboard where they go . . . although I usually do notice as the nuts approach the yoghurt that they are not supposed to be together and take the nuts back out of the fridge.  I also have off-and-on pain in the small joints of my hands and feet and in my sacroiliac joints.  I am also cold compared to everyone else and have to really restrict my diet to avoid gaining weight.  All of these symptoms stopped getting worse once I started phlebotomy, but did not get better and still haven't even though I am now de-ironed.  I wonder if these symptoms may reflect cellular damage caused by iron overload that doesn't repair itself, particularly neurons and cells in endocrine tissues, but this is just a guess.  So I haven't given up on figuring out the root cause of these symptoms and fixing whatever it is, but just getting rid of the excess iron didn't do the trick.

      One thing that may have gotten better:  during the time my ferritin was going up, my TSH climbed also, although remaining within the normal range, and my free T3 was low when my free T4 was within the normal range.  I have read that when the body isn't converting the (mostly inactive) T4 to the active T3, there is an excess of T4 that can cause rapid heart beat.  I haven't had any endocrine testing done since getting rid of my excess iron but my resting heart rate has dropped a bit, so maybe my thyroid parameters are better.  Or maybe my heart was affected by extra iron when my ferritin was high and now it isn't.  

      Also, because of the suspicion of celiac disease (more on that below), my bone mineral density was tested and I was found to have osteopenia.  I was really surprised by this because I take physiological doses of vitamin D3 as well as vitamin K (K2-MK7), and supplemental amounts of the (bio-identical) hormones estradiol, progesterone, and testosterone.  Osteopenia *may* be related to iron overload in ferroportin disease, because the spine is one of the places that iron can been seen to accumulate on MRI imaging.  I started taking potassium citrate and extra magnesium (let me know if you want medical references on this) and I am hoping my bone density will improve now that my iron levels are back to normal.  However, bone mineral density testing is allowed only once every three years, so I have another year or so to go before I find out.  Your ferritin didn't go as high as mine, but there are many different types of mutations involved in ferroportin loss-of-function disease so maybe some of these mutations are harder on bone than others?  Given spine pain, it may very well be worthwhile asking about your bone density - and definitely worthwhile if you have noticed any loss of height or getting a bit stooped-over.

      I would suggest keeping some sort of log to track your symptoms over time, because it is really hard to remember how tired you were or how much something hurt weeks, months, or years ago.  I track fatigue, using a scale of 0 (asleep) to 5 (normal.)  I haven't been "5" since I started tracking . . . with the exception of the morning after a surgery during which I was given a high dose of steroids.  (I have no idea why steroids would reduce fatigue in iron overload . . . but it was great feeling normal, except of course for the post-op pain, for the few hours that the effect lasted.)

      Symptoms that I have that I believe are completely unrelated to my iron metabolism are multiple food intolerances, including to gluten and/or something else in wheat.  Wheat/gluten exposure results not only in cramps, diarrhea, and a major increase in fatigue, but also causes one joint - a different joint each time - to suddenly turn red and hot and swollen and then gradually go back to normal over a week or so.  This type of joint flaring is called palindromic arthritis - probably "palindromic" because the joint involved is the same after the flare goes away as it was at the beginning.  As long as I manage to avoid wheat and its components entirely, I don't get these joint flares. My blood tests have been negative for celiac disease antibodies and I haven't had intestinal biopsies done because there is no way I am going to start eating wheat again (and you have to eat wheat so that your intestinal mucosa develops the characteristic lesions that are looked for with the biopsies.)  I think I developed these food intolerances because I have hay fever, meaning that my white cells are easily offended, and I had H. pylori.  H pylori infects the stomach and punches holes in gastric mucosa through which intact food molecules can presumably pass and offend white cells.  I managed to get rid of the H. pylori infection, but unfortunately, like elephants, offended white cells have very long memories.  At least I haven't developed any new food intolerances since clearing the H. pylori.   I mention these symptoms to illustrate that just because someone has iron overload doesn't prevent them from having something else as well - and maybe more than one something else. 

      I don't have the thick blood problem that Sheryl describes - I bleed very easily, which is very useful when having phlebotomies.  However, given how easily I bleed - for example, I bruise for no reason and have had bleeding complications after every surgery I have had - I think I may have some sort of as yet undiagnosed bleeding disorder completely separate from my iron overload disorder.  My bleeding tendency was the reason that I didn't have a liver biopsy done when iron overload was first considered.  On the plus side, my very heavy periods - probably the equivalent of having a phlebotomy every 6-8 weeks or so - probably protected me from iron overload for years, even causing me to be iron deficient off and on.

      I hope you're not sorry that you asked! - and that there may be some bits in here that are helpful for you . . . .

    • hemopatient123
      hemopatient123 GillianA

      Posted

      Thanks Gillian. I will check bone density. This may be the issue with the pain on my spine. Good recommendation.

      Also I am 38. I imagine you were older when first diagnosed which is likely why your ferritin was higher than mine.

      Also I read that the spleen is the primary iron storage point for those with ferroportin disease. The spleen filters old red blood cells the white blood cells for immune purposes. As a result, the filtering causes iron to build up there first, well before liver or elsewhere. Something to consider as part of evaluation.

  • GillianA
    GillianA hemopatient123

    Posted

    A high ferritin with a normal transferrin saturation in someone with no liver disease or inflammation and whose hemoglobin drops with phlebotomy is suggestive of one of the less common types of iron overload disorder, particularly ferroportin loss-of-function (LOF) disease, also called hemochromatosis type 4A.  In this disorder, which is inherited as an autosomal dominant (i.e., you get ferroportin disease if only one of the genes coding for ferroportin protein is abnormal), ferroportin can't export iron out of cells very well.  The result of reduced iron export out of cells is what you would expect:  the build-up of excess iron within cells.  

    Because the problem in ferroportin disease is not being able to get iron out of cells - unlike the iron overload in HFE hemochromatosis where too much iron is absorbed - the iron overload in ferroportin LOF disease occurs mainly in the cells of the reticuloendothelial system, mainly splenic and bone marrow macrophages and hepatic Kupffer cells (Pietrangelo 2006, Pietrangelo 2014).  There is a characteristic combination of high ferritin in the range of 1,000-5,000 ug/L (Beaton 2012) and, until late in the disease, normal transferrin saturation. (Pietrangelo 2014) 

    The reason that hemoglobin drops with phlebotomy in ferroportin LOF disease is that the extra iron needed to make more blood is inside those macrophages and other cells of the reticuloendothelial system, because these are the cells responsible for recycling old red blood cells.  Normally, these recycling cells take in old red blood cells, break down the old red blood cells and the hemoglobin they contain, and export the iron back out so that the bone marrow can use the iron to make new red blood cells.  But . . . . the only molecule that exports iron out of cells is ferroportin, and if your ferroportin is not working properly, it takes considerably longer than usual to get enough iron exported back out to make enough new red cells to be ready for another phlebotomy.  Therefore, you need to wait between phlebotomies for however long it takes for your hemoglobin to come back up. 

    Another possibility  when ferritin is high and transferrin saturation is not can also be seen in aceruloplasminemia. (Fleming 2012)

    References

    Beaton MD, Adams PC.  Treatment of hyperferritinemia.  Ann Hepatol. 2012 May-Jun;11(3):294-300.   http://www.annalsofhepatology.com/revista/numeros/2012/HP123-03-Treatment.pdf

    Fleming RE, Ponka P.  Iron overload in human disease.  N Engl J Med. 2012 Jan 26;366(4):348-59. http://www.trinity.edu/rblyston/documents/JAMPjanReading/Fleming2012.pdf ; Figure 3B (page 356 of the document, page 9 of the pdf) gives a suggested workup for iron overload based on high ferritin, and covers the situation where transferrin saturation is normal or low.

    Pietrangelo A, Corradini E, Ferrara F, Vegetti A, De Jong G, Luca Abbati G, Paolo Arcuri P, Martinelli S, Cerofolini E.  Magnetic resonance imaging to identify classic and nonclassic forms of ferroportin disease. Blood Cells Mol Dis. 2006 Nov-Dec;37(3):192-6. http://www.ncbi.nlm.nih.gov/pubmed/17052926  (abstract)

    Pietrangelo A.  The ferroportin disease.  Clinical Liver Disease 3.5 (2014): 98-100. http://onlinelibrary.wiley.com/doi/10.1002/cld.340/full

  • BikerBlue
    BikerBlue hemopatient123

    Posted

    Hi there,

    I feel your pain - I'm in exactly the same boat. No cause found for raised ferritin.

    I decided that maybe it is due to fatty liver - that can cause raised ferritin. My gastroenterologist said because my BMI is 28 that may be the reason - although I haven't had it confirmed on ultrasound scan. Also, alcohol can increase ferritin so I've given it up completely.

    Do you Stick to less than 21 units per week? I was only a moderate drinker (less than 14 units most weeks) but I'm wondering if even moderate alcohol can affect those of us with GH. A raised MCV can be caused by alcohol too.

    I'm going to ask my GP to check my ferritin again after a month of dieting and abstinence from alcohol - if that doesn't help I'll be stumped too!

    As I mentioned, my specialist refused to do venesection and has discharged me.

    The good news for you is that your organs are not storing iron (yet) so that is great. But because ferritin is an acute phase protein it is not specific which makes finding the cause really difficult.

    I think there are many things not yet understood about this disease.

    Let us know how you get on. Wishing you all the best in your treatment smile

    • hemopatient123
      hemopatient123 BikerBlue

      Posted

      Biker,

      I've had 10 drinks probably all year. I don't drink that much. My BMI is 23. I don't have a fatty liver as the MRI would have shown it.

    • BikerBlue
      BikerBlue hemopatient123

      Posted

      Hi,

      Sorry - I wasn't trying to accuse you, I was just thinking about trying to rule things out. I don't really believe I have that either but when the doctors keep telling you there is nothing wrong and your ferritin remains up it becomes very frustrating. Especially if you feel yourself that something is wrong.

      I hope you get to the bottom of things.

    • hemopatient123
      hemopatient123 BikerBlue

      Posted

      Thanks Biker. Didn't think you were accusing me lol. Just responding to your suggestions cause I ruled them out already. Thanks
  • sheryl37154
    sheryl37154 hemopatient123

    Posted

    My son is also C282Y/H63D (avoiding all the long words) but had the high TS% and can sustain frequent venesections.

    You say you determined you were C282Y/H63D, which leads me to ask if you actually had a genetic test which proves this?  Sorry if this sounds strange, but it is the use of your words "I determined", rather than saying "a genetic test revealed" of some such.

    I have even heard of drs determining the genetic outcome of someone with HH without doing a genetic test!  So wrong and incompetent of them.

    No doubt you have read previous posts regarding the ferroportin gene.

    i am C282Y/C282Y, with a ferritin level >999 at diagnosis (I was also donating blood), constantly had a high TS%, but no iron in my liver.  I had pain in left side chest for a year before diagnosis, which dissipated with venesections.  It would return when my ferritin shot back up for some reason.

    My pancreas and kidneys good too.

    Although deemed "deironed", I finally got on to a specialist cardiologist who requested an MRI on the heart (at my request - and I had to pay for it), which showed no deposits.  I was sure they would find some there.  However, he gave me the best advice ever - that even if they could see any, they can't drain it or cut it out - just keep having those venesections.  Which makes sense of course.

    What I have found in my search of research, is that via autopsies, they have found that iron particles (being hard thin sharp pieces of metal despite their size) do cut into the cells and cause scarring in the heart (on their way in, and on their way out on venesection).  Thus perhaps the pain and inflammation.

    Now my iron overload caused oestonecrosis of my hip bones - that is how I was finally diagnosed after 9 years of severe regular HH symptoms.  My blood was so thick with iron that it blocked up the fine capilliaries that feed the bone, so the bone died.  I really felt it was in my muscles too causing constant body pain.  It can be found in your bone marrow too.

    So for years after deironing, I was still suffering severe fatigue and body pain.  My blood was often very thick and black when they tried to venesect - often a long and arduous procedure.  Then one day, I though bug... this I am going to try "baby" aspirin to thin my blood.

    Within a week, I felt lighter, walked faster (wasn't dragging that ship's chain and anchor around with me) and pain free.  Did more during the day, though still crashed and burned early in the evening.

    I really feel that aspirin loosened up clogged iron deposits in my body and got it moving.

    I don't think you have mentioned your symptoms.

     

    • hemopatient123
      hemopatient123 sheryl37154

      Posted

      Hi Sheryl,

      Thanks for your message and all of these details. Good to hear you are pain free now. To answer a few of your questions, I had the genetic test on the HFE gene and that's how I know I'm compound heterozygous. I'm planning to have the genetic test on the gene related to ferroportin disease next week. My symptoms are 1) osteophytes on my spine and general spine/upper back pain that requires constant "cracking" or adjustment multiple times a day to relieve pain and pressure. 2) tachycardia. I've been to the emergency room 4 times this year with sustained tachycardia with roughly 140 beats per minute. I have had this many other times this year other than the times I went to the hospital.

      I will have to try to aspirin. I don't have thick blood as my hemoglobin was normal when beginning my venesections. I was able to give 500cc's with 7 minutes my first time. The blood flowed nicely and was a normal red color rather than dark and thick.

      Interesting that your son is compound heterozygous as well but could stand the venesections. I think the difference is he has a high TS% which makes his hemoglobin jump back quickly whereas for me I have a normal TS% and am struggling to get my hemoglobin back up between venesections accordingly. This point (normal TS%) is why I now believe I may have Type 4 hemochromatosis/ferroportin disease in addition to the type 1 that is already confirmed genetically. Bloodwork next week will tell

      This board is awesome

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