Hemochromatosis is a metabolic disorder where the body absorbs too much iron from the food
you eat.
This accumulation of iron leads to elevated iron in the blood and poisoning of tissues
in the liver, pancreas, heart, pituitary gland, joints and skin.
The root -chromat- actually refers to color or the darkening of the skin that happens
when iron is deposited into it.
If we take a close look at our red blood cells, we’ll notice that they’re loaded with
millions of copies of the same exact protein called hemoglobin, which binds to oxygen and
turns our blood cells into little oxygen transporters, and basically allow us to move oxygen to all
the tissues in our body.
If we take an even closer look at those hemoglobin proteins, we’ll find that they’re made
of four heme molecules, which have, right in the middle, iron.
This iron molecule is what binds to oxygen, so without iron, we probably wouldn’t fare
too well, right?
Right.
Normally, you actually lose a small amount of iron every day, about 1 mg, some in the
sweat, some in shedded skin cells, and some in shedded cells in the gastrointestinal tract.
Most of us, through the diet, take in 10-20 mg of iron every day, and absorb about 10%
of that, so 1-2 mg, which is perfect!
People with hemochromatosis, though, absorb an unusually high amount of iron, sometimes
as much as 4 mg per day, even though you probably only need about 1 mg to even out your losses,
right?
You’d think that absorbing more of something is good, but in this case, a net gain of about
3 mg a day comes out to about 1 g per year of excess iron in your body, leading to more
than 20 g by age 40!
Most of this iron you hold on to is deposited in your organs, most notably the liver, but
also in your pancreas, your heart, joints, skin, and pituitary gland.
This process of depositing iron into organs is called hemosiderosis.
But hey, a little hemosiderosis over the course of a lifetime never hurt anyone, right?
Wrong!
Unfortunately, all this extra iron does start doing some serious damage because iron in
the body is actually pretty good at generating free radicals through the fenton reaction.
The fenton reaction is where molecules of iron 2+ are oxidized by hydrogen peroxide,
producing iron 3+ and the hydroxyl radical and hydroxide ion as byproducts; now, iron
3+ can then be reduced back to iron 2+ via hydrogen peroxide again, creating a peroxide
radical and a proton, and then the cycle repeats, creating this like endless loop of free radical
generation.
So, over time, all these deposits of iron slowly damage the cells in the various organs
by free radical generation, which can cause cell death and then lead to tissue fibrosis.
Dang.
Usually, since it takes so long to accumulate and for damage to set in, it’s not diagnosed
until age 50 for men and usually 10 to 20 years after menopause for women, mostly because
women have one extra method of getting rid of iron, which is through bleeding as part
of the menstrual cycle.
Another, really important point that we skipped over, though, is why someone might absorb
more iron than normal in the first place.
Well, someone could have primary or secondary hemochromatosis.
Primary hemochromatosis is also sometimes called hereditary hemochromatosis, so I’m
sure you can guess that it’s caused by a gene mutation, and it is, specifically in
the HFE gene, which stands for High F-E, or iron, which is located on chromosome 6; this
guy usually helps regulate how much iron we absorb from food.
People with this autosomal recessive disorder have a defect or mutation, though, either
the C282Y mutation or H63D mutation, the former being more common.
This mutation specifically affects the absorptive cells in your small intestine, called enterocytes.
These guys are super important for absorbing all sorts of things, including iron.
One awesome thing about them though, is that they only move the iron they absorbed into
the blood when there’s a need to move it into the blood.
So basically they regulate how much iron goes into your blood from your intestine.
With this mutation though, these enterocytes aren’t as good at regulating the iron, so
most of the iron in your diet just goes right across from the gut through to your bloodstream,
overloading the blood with iron.
If hemochromatosis is brought on by some other means besides a genetic mutation, it’s called
secondary hemochromatosis.
An example of secondary hemochromatosis is through frequent blood transfusions.
When you get new blood through the transfusion, after about 120 days those red blood cells
die off and the iron they contain gets recycled, so each new bag of blood basically adds a
bag of iron to your body.
So lots of transfusions means lots of iron in the blood.
Depending on the organs that absorb the iron, different complications can crop up.
A lot of the iron gets deposited in the liver cells, so it makes sense that the liver sees
quite a bit of damage over time from fibrosis due to free radical damage.
For that reason, about 60% of cases leads to cirrhosis, and all this damage increases
the risk of liver cancer.
If it deposits in the pancreatic cells, individuals might develop type 1 diabetes mellitus from
destruction of beta islet cells, and patients might develop malabsorption from damage to
the exocrine pancreas that helps us absorb nutrients.
If the iron is absorbed into the skin, the accumulation of iron along with an increase
in melanin production, whose mechanism is not well understood, may give patients a bronze
pigmented skin.
If it’s absorbed into the heart muscle or myocardium, patients can develop cardiomyopathy,
which can later lead to arrhythmias.
It can cause gonadal dysfunction due to accumulation of iron in the pituitary glands that affects
the release of sex hormones.
This can cause things like amenorrhea in women, absence of menstruation, and testicular atrophy
in men.
And finally if it gets in the joints, it can cause degenerative joint diseases through
a process that is not well understood but might involve the accumulation of calcium
crystals.
Clearly, since iron’s high in the blood, blood tests will show high iron content.
The transferrin percent saturation will be high, which is basically how many binding
sites on circulating transferrin are occupied by iron.
Transferrin’s this iron transport molecule in the blood that stores up to two iron molecules
and safely transports it in the blood.
So 25% saturation means that 25% of total available binding sites of circulating transferrin
are taken up, if there’s more iron, then more binding sites will be occupied and percent
saturation will be higher.
Right?
If more sites are occupied though, the ability to bind more iron will be down right?
Because there’s less open sites.
And this is actually a lab test called total iron binding capacity, where a blood sample
is taken and tested to see how much more iron that blood can carry, this molecule though,
instead of transporting it in the blood, it stores it inside cells.
When these ferritin levels and storage of iron increase, it’s basically a signal to
the body that it has enough iron, so it doesn’t need to transport it around, and synthesis
of new transferrin molecules decreases.
A liver biopsy can be used to definitively confirm that iron’s been deposited in the
hepatocytes.
The iron will normally show up as brown spots inside cells, but this can be confused with
the brown pigment inside cells of older patients which are due to a pigment called lipofuscin,
which is from the normal “wear and tear” process of cells, and is the normal residue
left over from lysosomal digestion over time.
To confirm that this brown pigment is actually iron in liver cells, you’d use a Prussian
blue stain that shows the iron as blue on histology.
Treatment of hemochromatosis usually involves phlebotomy - literally blood letting like
the age old treatment for so many things.
In this case, red blood cells are taken until the serum ferritin and percent saturation
levels are lowered, and the iron load is decreased.
Deferoxamine is a medication that can also be used as a drug treatment.
Deferoxamine binds to free iron in the blood and makes it easier to get rid of via the
urine, which again decreases the iron load.
Alright, as a quick recap … Hemochromatosis is a metabolic disorder where too much iron
is absorbed by the body.
This can be caused by a primary genetic cause, where a defect in the HFE gene leads to abnormal
iron regulation by enterocytes, or by a secondary cause like spiking the bloodstream with too
much iron through frequent blood transfusions.
Hemochromatosis, can lead to liver, heart, pancreatic, gonadal and joint damage and can
cause bronzing of the skin.
The disease is can be managed by blood letting.