[ Post a Response | Hemochromatosis ]
Posted by Julie MacFarlane HH - you already know a lot more than I do about the classic adult onset HFE form of hemochromatosis. HFE - HH is also autosomal recessive (like JH) but it is caused by mutations in the HFE gene on chromosome 6. If the HFE form of hemochromatosis is inherited in your family, then it is the HFE gene mutations that are being passed down through the generations. So even if a young person presents in the family, they likely have an earlier presentation of the HFE form since that is what the family history suggests. Genetic testing will determine this. There are always exceptions to every rule as you all frequently point out in your discussions. The latest research is showing that clinically, it is best to think of hemochromatosis as a "spectrum" of iron overload rather than separate diseases. JH individuals load iron faster and earlier and thus will present with clinical symptoms typically before 20 (range 10-30). Type 3 hemochromatosis caused by mutations in yet another gene (called TFR2) can present in individuals older than typical JH but younger than typical HFE-HH (range 30-50). And then there is HFE-HH with the typical clinical features presenting in 40's-60's. Now this is based on symptoms. So you can easily see the spectrum pattern and overlap arising. And if people are being diagnosed earlier because of family history and genetic testing, then there are more people today in the 20's , 30's and 40's with HFE hemochromatosis but that is because of earlier testing. This is a good thing ! Identifying these people early means that perhaps only biochemical iron loading has occured (higher ferritin, higher TS%), and starting therapy now will alleviate or prevent most of the symptoms that would have appeared later in life. So the more awareness we all create, the more we have to re-write the textbooks to change the clinical description of the disease. The other complicating factor in all of this is when you try to combine the genetic status to clinical status: some individuals who inherit the HFE gene mutations and are therefore "genetically affected" go on to develop biochemical iron overload and become "clinically affected" with hemochromatosis, while others do not. This is what is called reduced penetrance. HFE hemochromatosis has a lot of controversial reduced penetrance discussion in the literature, some saying that only 1% of those inheriting 2 HFE mutations go on to develop the disease. Others say it is more like 40-70% go on to develop the disease. The controversy lies in the definition of disease. The 1%-quoted researcher used severe disease features such as liver fibrosis or cirrhosis. Others define the disease more moderately by biochemical iron overload (high ferritin , high TS%), before such liver problems occur. So there is much still to do in researching hemochromatosis in regards to why some people go on to manifest the disease while others do not. And why some people manifest symptoms earlier than others, even in the same family. Keep up the very impressive newsboard discussion. I have learned a lot from you all. I welcome any feedback either via the newsboard or you can contact me directly via the CHS office.
on 11/1/2005, 1:37 pm
209.139.213.1
Hi all,
I have been frequently reading your newsboard with great interest for a long time now. I joined the CHS Board of Directors earlier this year and i am a certified genetic counsellor. So i hope it's ok that I add in my two bits about your ongoing discussions of HH and JH and how to tell them apart.
The challenge in describing all the different forms of hemochromatosis is that a lot of people - laypersons, researchers, medical professionals - may not clearly distinguish between the genetic description or the clinical description.
Genetic description: JH and HH are two different genetic forms of iron overload. JH is caused predominantly by mutations in the hemojuvelin gene on chromosome 1, and less frequently by mutations in the hepcidin gene on chromosome 19. JH is autosomal recessive - requiring 2 copies of the mutated gene to be passed down (one from each parent). JH has been reported all over the world (Western and Eastern Europe, Asia, Australia, USA, Canada). Unlike HFE-HH, JH does not have a N. European /Celtic association. There may be a higher frequency of JH in Italian, Greek , and French Canadian populations, but it is too early to confirm that. JH genetic testing is being offered in Vancouver (BC Womens and Children's hospital). For a very thorough review on JH, look at http://www.geneclinics.org and type in the disease name under "reviews".
Clinical description - because a younger person in the family has an earlier presentation of the HFE form of hemochromatosis , some people mistakingly call it "JH" because the person is young. This is incorrect. The term JH should only be used to describe the genetic disease called JH. This younger person with HFE-hemochromatosis may have been identified at a younger age because of increased awareness in the family (ascertainment bias).
Exceptions to all this: some of you point out that carriers of HFE-HH (inheriting only 1 mutation out of 2) manifest the disease and this shouldn't happen if carriers are supposed to be healthy. There are two likely explanations for this: 1) the person is really not just a carrier of the one HFE mutation. They have a second mutation, so the two together is resulting in their condition. The 2nd mutation could be in HFE(one that we typically don't screen for), or could be in a different gene such as hemojuvelin or hepcidin, or could be a gene that we have yet to discover. There are a few reports in the literature where patients have been found to have one mutation in HFE and one mutation in hepcidin or hemojuvelin. This is called digenic (two genes) inheritance. It is considered very rare but does exist. The second explanation (and the more likely of the two) for why a so-called HFE carrier would manifest symptoms is environmental reasons: lifestyle (ie. diet,alcohol intake,weight) or many other compounding diseases, can in some cases tip a person's genetic status "over the edge" to result in symptoms.
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