Do I have haemochromotosis??

Hi GillianA - could you please explain further the concept of having one normal C282Y and abnormal C282Y gene.  In the 19 years since my diagnosis and all the reading up of reseach of haemochromatosis and talking to researchers and listening to their addresses about haemochromatosis, this has never been mentioned.

Homozygous and heterozygous are carriers, but heterozygous are generally described as ONLY carriers, with one HFE gene.

Ferroportin is a diffferent issue and I don't know anything about it all as it does not apply to genetic haemochromatosis, and I only know what you have described in this forum.  However, there is such a problem as metabolic syndrome that can cause high ferritin levels without the transferrin saturation % being high, which Rebecca could ask her dr to investigate.

I really don't know what Gene my aunty has. But everything else you said sounds interesting. I'll look into it all. I get test results back this week to either rule out or find out if I have haemochromotosis.

Thanks, Sheryl, that really wasn’t a very clear summary – let me try again with a more detailed summary.  Is this better?  If anything still doesn’t make sense, tell me, and I’ll try again . . . Gillian

Inflammatory conditions (high ferritin, normal or low transferrin saturation): 

Inflammatory conditions (which include metabolic syndrome, usually defined as 3 or more of high blood pressure, body fat around the waist, high blood sugar, high triglycerides, low HDL [i.e., good] cholesterol) will raise ferritin even if iron levels are normal or even low.  This is probably an ancient defense against infection in which the body sees inflammation – no matter what is causing it – and thinks, “Incoming evil bacteria!!”  It then hides as much of its iron as it can inside its cells, especially inside its macrophages (= recycling cells) so that invading bacteria, who need iron to reproduce, can’t get at it.  I’ve read that 90% of the time when ferritin is elevated, the cause is inflammation, not iron overload.  Besides metabolic syndrome and infection, other causes of inflammation include too much alcohol, obesity, diabetes, liver disease, malignancy, autoimmune disease, chronic kidney disease, and more.  High ferritin caused by inflammation is usually accompanied by normal or even low transferrin saturation.  Common tests for inflammation of any type are the sedimentation rate (sed rate) and c-reactive protein (CRP.)

Types of genetic iron overload – there are 4 main types (plus a bunch of rare kinds):

Type 1 hemochromatosis (high ferritin, high transferrin saturation, liver cell iron overloading)

The most common form of inherited iron overload disorder, Type 1 hemochromatosis, involves mutations of the HFE gene.   (HFE stands for “High Iron” with Fe being the symbol for iron.)  The most common mutations of the HFE gene are called C282Y, H63D, and S65C.  The HFE gene provides instructions to the cell on how to make the HFE protein.  The HFE protein works with the cell to keep track on how much iron there is in the body.  If the HFE protein detects that iron levels are getting too high, it triggers an increase in the protein hepcidin, which then acts to stop the protein ferroportin from working, which then reduces iron absorption into the body.  This means that when the HFE protein isn’t working properly or there isn’t enough of it, it doesn’t shut off iron absorption when it should.  This leads to iron overload with high ferritin and high transferrin saturation.

A few definitions:  when two genes are called homozygous it means they are the same, and when they are called heterozygous, it means they are different.

Except for egg and sperm cells (which have 1 of each gene) and platelets and mature red blood (which don’t have nuclei), the cells of our body all have 2 of each autosomal (not sex-related) gene – and two sex-related genes - two X genes for (most) females and an X gene and a Y for gene for (most) males.

If a disease or condition is caused only when you have the mutation on *both* non-sex-related genes (homozygous mutation), then it is called an autosomal *recessive* condition.  With an autosomal recessive condition, if you have a mutation on only one gene, then you will be a heterozygous “carrier” – you won’t be affected but there is a 50% chance you will pass the mutated gene along to each of your children.  A child who gets the mutated gene from you will also be a heterozygous carrier and won’t get the disease or condition – unless the other parent is also a carrier of the same mutation and also passes the mutation along, which would mean the child would then be homozygous for the mutation and would be affected. 

On the other hand, if a disease or condition is caused by one mutated non-sex-related gene even when the other gene is normal (heterozygous mutation), then it is autosomal *dominant*.  If you have an autosomal dominant disease or condition, there is the same 50% chance for each of your children that you will pass along the mutated gene, but with dominant inheritance, any child who gets the one mutated gene will be affected. 

In the case of the HFE gene, you can have a C282Y mutation on one HFE gene and not on the other one (= heterozygous mutation) or you can have C282Y mutations on both HFE genes (= homozygous mutation) or you can have no C282Y mutation on either gene (homozygous normal).  Similarly, you can be heterozygous (one mutation) or homozygous (two mutations) for H63D mutations, and the same for S65C. 

You are more likely to get iron overload with elevated ferritin AND elevated transferrin saturation with liver iron overload if your two HFE genes have:

·         TWO C282Y mutations (homozygous – autosomal recessive inheritance),

·         TWO H63D mutations (homozygous – autosomal recessive inheritance; milder than C282Y homozygotes),

·         one C282Y mutation AND one H63D mutation (= compound heterozygous, so two-gene inheritance, also milder),  

·         ONE S65C mutation (heterozygous – autosomal dominant inheritance, milder).

Not everybody with the same type of HFE mutations gets the same degree of iron overload and some don’t get iron overloaded at all, so there must be a lot of other factors involved, including things like iron intake, regular blood loss (e.g., having periods, regular blood donation, etc.), and probably the effect of other genes that regulate iron metabolism.

The other main types of genetic hemochromatosis are:

Type 2 Hemochromatosis (high ferritin, high transferrin saturation, liver cell iron overloading)

Type 2 hemochromatosis, aka juvenile hemochromatosis because it affects people at a younger age, is caused by mutations in either the HFE2 or HAMP gene.  It is autosomal recessive.

Type 3 Hemochromatosis (high ferritin, high transferrin saturation, liver cell iron overloading)

Type 3 Hemochromatosis is caused by mutations in the TFR2 gene.  It causes iron loading similar to HFE hemochromatosis but generally more severe and starting earlier in life, usually before age 30.  It is autosomal recessive.

Type 4 Hemochromatosis, aka ferroportin disease, caused by mutations in the SLC40A1 gene (and a few related genes).  There are two kinds of ferroportin disease, both of which are autosomal dominant:

Type 4A:  (high ferritin, normal or low transferrin saturation, macrophage [recycling cells] iron overloading)

This is a less severe form of genetic hemochromatosis caused by ferroportin underactivity (“loss of function”) that both reduces absorption of iron and also impairs the cell’s ability to get rid of iron.  The resulting iron overload affects iron recycling cells and causes ferritin to go up but not transferrin saturation.  Hemoglobin tends to be on the low side, and it takes longer for hemoglobin to recover after phlebotomy because it takes longer for the impaired ferroportin to get the extra iron out of the iron recycling cells so it can be made into new red blood cells.

Type 4B:  (high ferritin, high transferrin saturation, liver cell iron overloading)

This is a more severe form of genetic hemochromatosis caused by ferroportin overactivity (“gain of function”) that increases the body’s absorption of iron.  It causes iron loading similar to that caused by Type 1 Hemochromatosis.

And then there are all kinds of other less common genetic causes of iron overload.

I’ll mention one of the less common genetic causes of high ferritin, HHCS benign hyperferritinaemia, because even though ferritin can go quite high with this condition, iron overloading doesn’t happen and transferrin saturation remains normal.  With this cause of high ferritin, because there isn’t any iron overload, phlebotomy isn’t needed or tolerated:

HHCS Benign hyperferritinaemia (high ferritin, normal transferrin saturation, tissues don’t get iron overloaded, some people with it get cataracts and some don’t)

This is caused by mutation in the L-FT and L-FT IRE genes.  (not much published on this one – best article I found was Camaschella and Poggiali, Haematological March 2009)

Hi GillianA, that is a very good detailed explanation for those who do not know much about haemochromatosis.  However, I do know all of that.  It was your statement/question regarding "one abnormal C282Y gene and one normal C282Y – or one abnormal H63D gene and one normal H63D?" that I am querying.

Your above explanation does not touch on that - and it is something that I have never found in all the research that I have read.  We are homozygous  with two HFE genes, or heterozygous with one HFE gene only, but I have never heard of having one "normal" and one "abnormal" gene when we are homozygous.

I am sure that you know that is not possible, and perhaps it was just bady written.

I was wondering if u could read my write up on Not Sure What To Do. As my dr has virtually no idea what is Haemochromotosis and doesnt want to go any further to investigate wats going on. Thanks

We each have two HFE genes, one on each of our two chromosome 6’s.  The HFE gene contains instructions telling the cell how to make the HFE protein.  Each one of our two HFE genes may be normal with no mutations OR it may contain one or more mutations.  Apparently about 20 mutations of the HFE gene have now been identified that affect the 3-D structure and function of the HFE protein.  Other mutations of the HFE gene have been identified, called “silent” mutations, that don’t cause any problems with the HFE protein.  The C282Y mutation of the HFE gene has a worse effect on the function of the resulting HFE protein than do the H63D and S65C mutations.  (And that’s just the HFE gene; each person may or may not have other mutation(s) on other genes that code for proteins affecting iron metabolism, which is why the current research using whole genome analysis to look at iron overload disorders is so interesting.  I’m not sure why so much information posted online uses the term “hereditary hemochromatosis” as if HFE C282Y homozygosity were the only possible type of hereditary hemochromatosis . . . it’s confusing, especially for those of us who have other types of hereditary hemochromatosis.)

I was trying to put the notation for HFE gene mutations into words – e.g., 

homozygous for HFE C282Y – one C282Y mutation on each HFE gene, which is written as C282Y +/+

heterozygous for HFE C282Y, which is written as C282Y +/-

homozygous normal (wild-type) on the HFE gene at the location where the C282Y mutation occurs, which is written as C282Y -/-.

Similarly, at the H63D location on the HFE gene there can be H63D +/+, H63D +/-, and H63D -/- .  For S65C, there can be S65C +/+, S65C +/-, and S65C -/- .

Compound heterozygosity for C282Y and H63D would be written as:  C282Y +/-, H63D +/-.

And compound heterozygosity for C282Y and S65C would be written as:  C282Y +/-, S65C +/5.

Rebecca said her great aunt was a carrier for hemochromatosis.

This tells us that Rebecca’s great aunt won’t have a S65C mutation on her HFE gene because S65C is autosomal dominant.  Therefore if the great aunt was heterozygous for S65C ( S65C +/- ) she wouldn’t be a carrier, she would be affected. 

Similarly, Rebecca’s great aunt won’t have either type of Hemochromatosis Type 4, the ferroportin diseases, because they also show autosomal dominant inheritance.  If the great aunt had one of the gene mutations that cause Hemochromatosis Type 4, she wouldn’t be a carrier, she would be affected.

So, trying again – is this wording better - ?

“When you say your great aunt is a carrier of haemochromatosis, do you mean she was told that she had a C282Y mutation on one (but not both) of her HFE genes, or that she had a H63D mutation on one (but not both) of her HFE genes?” And to be complete, I should add, “or a mutation of some other iron-related gene with autosomal recessive inheritance?”

"  I’m not sure why so much information posted online uses the term “hereditary hemochromatosis” as if HFE C282Y homozygosity were the only possible type of hereditary hemochromatosis . . . it’s confusing, especially for those of us who have other types of hereditary hemochromatosis.)"

The reference to Hereditary hemochromatosis is to separate this genetic disorder from those with with high ferritin caused by other health issues, often called hemochromatosis too by drs who don't know any better.

The information posted online that you refer to is more than that.  World reknown researchers verbally state their belief that only homozygosity C282Y causes iron overloading bad enough to cause health problems.  It does make some of us bristle when we hear this at conferences, because in my case, I have a son who is compound heterozygous C282Y/H63D and his ferritin level was 772 when he was 22 (tested after I was finally diagnosed), and because my son once he left home was rather slack with the timing of his venesections has gone on to have the usual health problems associated with HH.  My husband, his father, is homozygous H63D and had a ferritin level of 557 when diagnosed.  He was asymptomatic although he went on to have Hodgkin's Lymphoma for which there is no proven cause.  He had a few venesections to reduce his ferritin level to 30 something and then no longer loaded iron (after chemo and radium).  Another couple in the audience have a son with the same compound heterozygosity and he had health issues.

S65Cs don't rate a mention as it is deemed totally harmless, except that it is acknowledged that it is another known HFE gene.  It is recognised that there are other factors involved to cause some people to load iron and others to not.  Too many drs commonly believe in the 'not likely to load iron' factor, and will never know nor wish to know the detail that you have gone into.

It is like herding cats to get them to know the basics.  And at conferences regarding hereditary hemochromatosis, I am afraid that ferroportin disease does not get a mention.  And there are no questions from anyone present regarding ferroportin disease.

With heterozygosity, there is only one HFE gene, because either one parent does not have any HFE genes, or is heterozygous themselves, meaning their parents did not pass down two genes, and that person only inherited one gene (from the other parent).  There are not two HFE genes, only one in heterozygosity.  C282Y -/- means totally negative for C282Y HFE genes.  + is positive for that gene, - is negative for that gene.   C282Y -/- (refered to as wild type) are those people without any C282Y or any known HFE gene at all and are used in research to be able to compare results against those who are homozygous C282Y +/+ and heterozygous C282Y +/-.  Maybe families could carry some other gene not yet identified in genetic tests, because it is of no consequence to loading iron.  To bring this possibility into the equation is too confusing to those who are trying to get a grasp on the basic or working knowledge of haemochromatosis.  Eventually when they get that sorted out, they may want to search research further like you and I have done.

Hopefully, one day they will find what causes our hepciden to not turn on to turn off the loading of iron.  It could be another gene, or other factors.  Strangely progesterone is on the list, along with others only identified by alpha-numerals.  But I have taken progesterone as HRT, and it did not turn on my hepcidin.  And progesterone in increased quantities causes too many hormonal problems.

There is a world reknown HH researcher in Canada call Prof Paul Adams in Ontario I think.  I have spoken to him at a conference.  Have you tried to contact him to see if he can help you with ferroportin?

Good luck with getting some support.

Hi Sheryl,

I’m sorry to be so late replying – it’s been a zoo around our place lately.

I think you have hit the nail on the head when you say that the false belief that C282Y homozygosity is the one and only genetic cause of iron overload bad enough to damage health is a huge problem.  Rheumatologists and haematologists who practiced before 1996 – when the C282Y mutation of the HFE gene was discovered – know better, because they were treating patients who were iron overloaded based on clinical presentation and response to phlebotomy.  Researchers and clinicians who published after 1996 on iron overloading caused by other mutations of the HFE gene and mutations of other genes also know better.  And people like you and me who have ended up having to dig into the medical literature ourselves also know better. 

But, as far as I can tell, doctors and patients are out of luck if they want to find a clear, succinct posting covering different types of hereditary haemochromatosis that *doesn’t* in some way reflect the false beliefs that “hereditary iron overload = C282Y/C282Y” and “if you aren’t C282Y/C282Y (or maybe C282Y/H36D), then you don’t have hereditary iron overload.” 

Obviously, this has gone on far too long and somebody has to do something about it – probably a whole bunch of somebodies, but I thought I’d start with me.  I’ve gone to the patient.info professional reference on hereditary haemochromatosis and entered feedback urging that the posting be rewritten to clearly and consistently reflect our current state of knowledge about inherited iron overload disorders, including the limitations of our current state of knowledge.  I’m may end up being sorry about this, but I’ve also offered to help with a rewrite.  We’ll see what happens . . . .

Hi Gillian

Just read patient.info regarding haemochromatosis for the first time.  I read so much about it but try to stick to research studies now for advanced knowledge.

There are a couple of things that stand out to me.

"but the clinical penetrance of the mutation is much lower than the genetic prevalence."  I have yet to see the real stats on that.  Most often if people don't have the symptoms, they are not genetically tested.  And I always say YET!  Because our body make up can change with other health issues, environment, etc.  Something can trigger what ever is necessary to turn off the hepcidin control.  So these people should always be monitored.  Sometime down the track, their health can change, but it will be quoted "Oh, but it has been recorded that you don't have clinical penetrance, etc.

Governments and medical associations cling to that statement to avoid the cost of screening.  However, a study in Australia of the cost of treatment of late diagnosis of haemochromatosis, outweighs the cost of screening.

Everything I have read is that one in 200 people of Northern European descent can have the HHC genes, one in 7 are carriers. Also, it is not just Northern Europeans, Portuguese and Spanish have the same high incidence of haemochromatosis.  In fact, people from there are mostly the ones that migrated to Ireland long ago carrying the haemochromatosis genes.

Somewhere it says, men are affected more by haemochromatosis than women.  This is a myth.  It is only because most often the women are not diagnosed until after menopause (or hysterectomy), and even then the symptoms are put down to menopause rather than be investigated further.  So women are suffering a double whammy at that time.  (It took 9 years for me to get a diagnosis after a hysterectomy, and even then after my hip bones broke up from osteo-necrosis caused by too much iron in my blood).

All these changes must be backed up by references though, and that is the hard part, wading through heaps of research studies.

All the best of luck to you - I hope you are successful.

Hi Rebecca,

You mean you found out that you're not iron overloaded, and something else is causing your ferritin to be high?  I hope whatever it is is easy to fix and you feel better soon!

Best wishes,

Gillian