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Hi clare1966

I am homozygousCys282Tr HFE related HH.

And I am told I don't need to know just bleed... *gulp*

It is it seems, complex and confusing, at least to me.

How life has changed since July. But my numbers are begining to drop and I can see a way forward . I hope we both will find answers soon. Good luck.

Me too Clare, I was diagnosed 2 months ago with hereditary Haemochromatosis ( homozygous for C282Y mutation) all I know is that I have had this since birth and inherited it from one or both parents.. I had a ultrasound on my liver and other organs to check the ferritin in the blood hadn't done any damage and I started venesections soon after, I have now had 4 treatments ( fortnightly ) and have yet to find out if the levels have gone down, that is all I can tell you, but I'm sure that there will be someone on here that can help with the technical side for you!

Best wishes xx

Hi Clare, I’m not sure what kind of layman’s explanation you’re looking for – but just in case, this is my best attempt to explain what I understand about chromosomes and hereditary iron overloading.  It would be a good idea to run this by your doctor to make sure I’ve got it right.

Almost all cells in the body contain chromosomes.  (A few types of cells don’t, such as red blood cells and platelets.)

The body cells that do contain chromosomes each contain 23 pairs of matched chromosomes, making 46 chromosomes in all:  two chromosome 1’s, two chromosome 2’s, two chromosome 3’s, and so on.  (Egg and sperm cells each contain only a single set of 23 chromosomes.  When the egg and sperm come together, the fertilized egg cell matches up the 23 chromosome from the egg and the 23 from the sperm and goes back to containing 23 pairs of chromosomes again.)

Of the 23 pairs of chromosomes in regular body cells, one pair is the sex chromosomes, either XX (for females) or XY (for males.)  The Y chromosome is shorter than the X chromosome.  The other 22 pairs of chromosomes have two chromosomes that are normally the same length.

Every chromosome is made up of two very long strings of DNA (the molecules of genetic coding, all lined up like beads on the string.)  The chromosomes are tightly coiled up to make them smaller.  The two chromosomes in each matched pair are tacked to each other not quite in the middle at a spot called the centromere.  When you see pictures of chromosome pairs, each pair looks rather like a fuzzy “X” with one arm of each chromosome a bit shorter than the other arm.  Usually the chromosome pairs are shown with the short arms pointing up.

About chromosome 6

Now let’s take a closer look at the chromosome pair that is made up of two chromosome 6’s.

On the short arm of each chromosome 6 there is a chunk of DNA that makes up the HFE gene.  (HFE is short for High Iron Fe, where Fe is the chemical abbreviation for iron.)  The HFE gene tells the cell how to make HFE protein.  HFE protein, in turn, tells the cell how much hepcidin to make.  Hepcidin’s job is to tell the body when it has enough iron and to cut back on iron absorption so iron overload doesn’t develop.  Therefore, if you have too much hepcidin, you don’t absorb iron very well (but your iron recycling cells get overloaded.)  On the other hand, if you don’t have enough hepcidin, then you can absorb way too much iron and get really iron overloaded. 

About C282Y

On chromosome 6, in the HFE gene at position 282, there is supposed to be the amino acid cysteine.  When there is a C282Y mutation, the cysteine (C) that is supposed to be there is replaced by the amino acid tyrosine (Y), which isn’t supposed to be there.  When the tyrosine replaces the cysteine at position 282, the HFE gene doesn’t make HFE protein properly.

When someone is *heterozygous* for C282Y, they have a C282Y mutation of the HFE gene on one chromosome 6 but no C282Y mutation of the HFE gene on the other chromosome 6.  In this case, assuming that no other mutations are involved, the normal HFE gene produces its usual amount of HFE protein as required but the HFE gene with the C282Y mutation doesn’t.  This isn’t usually a major problem, because one normal HFE gene all by itself can make pretty close to all the HFE protein that the body needs.  Therefore, people who are heterozygous for C282Y (if they don’t have any other mutations that contribute to iron overloading) tend to have higher iron levels than people with no C282Y mutations, but they don’t usually get iron overloaded.

However, when you are *homozygous* for C282Y, you have a C282Y mutation on each one of your HFE genes.  This means that your body will not be able to make enough HFE protein and will therefore be low on hepcidin.  Without enough hepcidin to tell your body when to cut back on iron absorption, you are prone to absorbing too much iron and to keep on absorbing iron even when your body is already iron overloaded.

The solution to having the tendency to absorb too much iron is to have a way to get rid of it.  The most obvious way is through bleeding, because red blood cells contain iron.  Regular menstrual periods or donating blood regularly will usually prevent iron overload from developing.  However, once someone is iron overloaded, bleeding has to be done frequently – usually weekly, at least to start – in order to get rid of the excess iron.  This is often called “de-ironing.”

Extra for experts: 

There is another mutation of the HFE gene, called H63D, in which the histidine that is supposed to be at position 63 of the gene is replaced by aspartic acid.  Having a H63D mutation also reduces the production of HFE protein and of hepcidin, although not as much as having a C282Y mutation.  Being homozygous for H63D does increase iron absorption and can occasionally cause iron overloading (6.7% of people who were homozygous for H63D became iron overloaded in one study in Newfoundland and Labrador, Canada.)  People who have one C282Y mutation plus one H63D mutation (called “compound heterozygote”) can also get iron overloaded, I’m guessing probably less than someone with two C2826 mutations but more than someone with two H63D mutations. 

There are also other mutations of the HFE gene and of other genes (non-HFE) that cause iron overloading.  Usually testing is not done for these other mutations except in research studies.  Mutations on the HFE gene that cause iron loading are grouped together as Type 1 (HFE) hemochromatosis.  Other types of genetic hemochromatosis include Type 2 (juvenile hemochromatosis, which is subdivided into 2A and 2B), Type 3, Type 4 (ferroportin disease, which is subdivided into 4A and 4B), hypotransferrinemia, and aceruloplasminemia.  And they keep finding more gene mutations that affect iron metabolism all the time.

And then it starts to get really complicated, so I’ll stop here . . . .

I’m homozgous c282y found your explanation so interesting, makes you wonder what some of the doctors do and don’t know . I had 37 weekly VS and down from 1900+ to 50, but I do have cirrhosis of the liver due to undiagnostics but I apart from arthritis probs all my life I’m 60 and pretty fit. Advice is to always stay positive. Thanks & good luck to all