Hemochromatosis is a fairly common genetic disease that causes iron to build up in the body. Knowledge is power here! Knowing that you carry the genetic variants for hemochromatosis can literally add years to your life since you can prevent the buildup of iron by giving blood.
23andMe and AncestryDNA genetic data can tell you if you likely carry the more common genetic mutations in the HFE gene for hemochromatosis. First, an explanation of iron in the body, and then I’ll explain how to check your genetic data to see if you carry the HFE mutations. Finally, I’ll explain testing options and ways to decrease high iron levels.
What is hemochromatosis?
Hemochromatosis is the disease state of building up too much iron in the body. It can be caused by genetic mutations in iron-related genes, or it can be due to excessive blood transfusions for anemia or liver disease.
Iron is essential – but needs to be in just the right amount. People with hereditary hemochromatosis absorb more iron from food than they should due to genetic variants.
Once iron gets absorbed in the intestines, the body doesn’t have a good way to get rid of it. Normally, the body tightly regulates the amount of iron absorbed. When a little bit too much iron is absorbed, such as for people carrying genetic variants that cause hemochromatosis, the excess builds up over time. The body stores the excess iron in the organs, including the liver, heart, pancreas, skin, pituitary, and thyroid. You also can store iron in your joints and bone marrow.[ref]
What are the symptoms of hemochromatosis?
Symptoms of building up too much iron can include:
- joint pain
- abdominal pain
- liver disease
- irregular heartbeat
- bronzed skin color
- elevated blood sugar and more.
Why do we need iron?
The body uses iron in numerous ways. In fact, every cell in the body uses iron in one form or another. Iron, involved in redox reactions, moves electrons in the mitochondria to produce energy. Also, red blood cells need iron as a critical component for moving oxygen throughout the body.
When you think about iron out in nature, rusty old iron parts may come to mind. Rust forms because iron can be easily oxidized, forming compounds with oxygen. This ability to move electrons around makes iron incredibly important – and also incredibly reactive – in the body.
Regulating Iron in the Body:
The body regulates the absorption of iron tightly. Not only do we not want too much oxidation occurring in the wrong place (no ‘rusting’ in the body ;-), but our body also regulates iron to keep it away from iron-loving bacteria. Certain pathogenic species of bacteria thrive and multiply rapidly when iron is available. Thus, we don’t want too much iron in the body, and we have ways of quickly sequestering, or storing, the iron when the body is fighting off a pathogen.[ref]
The liver produces the iron regulatory hormone called hepcidin. Discovered and named in 2000, and scientists have since figured out that hepcidin controls the regulation of iron in the body and responds to lipopolysaccharides, a component of bacteria, to prevent iron-loving bacteria from reproducing rapidly.[ref]
The HFE gene was discovered in 1996 and is linked to hereditary hemochromatosis. This gene codes for a protein that controls how iron is taken into the intestinal cells. Free iron is bound to transferrin, which then binds to a transferrin receptor in order to be taken into the cell. HFE can also bind to the transferrin receptor, blocking the receptor from taking iron into the cells. In this way, HFE is a negative regulator of iron absorption.[ref] HFE as an iron sensor controls the intake of iron and regulates the downstream production of hepcidin.[ref]
When there is too much iron absorbed, whether because of a mutation in the HFE gene or other genes regulating iron, the body stores it in different organs. Excess iron causes oxidative stress and DNA damage to the tissue. This can cause fibrosis and cell death, leading to cirrhosis of the liver or other organ damage.[ref]
How do you inherit hemochromatosis?
There are multiple causes of hereditary hemochromatosis. The most common cause is a genetic variant that impacts the HFE gene. This allows too much iron to be absorbed into the body and is called type 1, or classic, hemochromatosis.
Other rare causes of hemochromatosis include variations in other genes involved in hepcidin regulation and in the transport of iron. These are known as hemochromatosis type 2, 3, and 4.
Interestingly, hemochromatosis was first described in the 1700s as ‘bronze diabetes’ or ‘pigmented cirrhosis. This refers to the way iron accumulating in the skin can make it look bronzed, along with the damage to the pancreas causing diabetes or the liver causing cirrhosis.[ref]
How rare is hemochromatosis?
The HFE mutations are much more common in people of Northern European heritage. But, not everyone who carries the variants will end up with a diagnosis of hemochromatosis.
Estimates show that ~10% of people of Northern European ancestry carry one copy of an HFE variant (more on this below). It is thought that the main hemochromatosis mutation (HFE C282Y) originated in the Celtic or Viking population before 4,000 BC. From there, it spread through the European population. [ref]
Studies on hemochromatosis vary quite a bit in their estimates of how common hemochromatosis is amongst people with the variants, and this is mainly due to differences in the clinical definition.
Some define hemochromatosis as having a ferritin (measure of storage iron) level of over 1,000 mcg/l — along with liver disease, heart failure, and bronzed skin. Others define hemochromatosis as having elevated ferritin (>300 mcg/l) along with liver failure.[ref]
The question, then, is whereupon the spectrum of organ damage do physicians define hemochromatosis – is just having the pancreas damaged and causing diabetes enough, or do you also need liver damage? The clinical diagnosis and research study definitions vary quite a bit.
But this website is all about optimizing health, so let’s look at what happens to the body before your liver fails…
Problems with excess iron well before a hemochromatosis diagnosis:
As you can imagine, the symptoms of iron building up can occur over the decades leading up to the point of organ failure.
Symptoms of excess iron include:
Joint pain, fatigue, and irritability are common complaints in people with HFE genetic variants.
Reduced libido and erectile dysfunction in men is common with iron build up. [ref]
Diabetes and heart disease diagnosis also can often precede the clinical diagnosis of hemochromatosis.[ref]
The key here is that all of these problems due to excess iron can be prevented.
You aren’t destined to have aches and pains leading up to liver failure or diabetes — knowledge is power here and iron levels can be reduced. (More on this in the Lifehacks section below).
HFE and the Immune system:
While iron is essential for transporting oxygen throughout the body, it also can be essential for bacterial growth. As I mentioned above, many bacterial species thrive in iron-rich environments. One major role of iron regulation in the body through iron storage via ferritin to sequester iron away from bacteria. [ref]
While iron regulation and the HFE gene are important in bacterial infections, it turns out that HFE may play a role in the immune system that is not related to iron. In fact, researchers initially classified the HFE gene as part of the HLA system. [ref]
Research shows that a protein in the HIV virus significantly downregulates the HFE (iron homeostasis) gene.[ref] Researchers have also found that infection with cytomegalovirus also decreases HFE through degrading the protein.
The question for researchers has been ‘How does interfering with iron and downregulating the HFE protein help viruses to reproduce?’.
It turns out that the answer may be that HFE plays a role in the innate immune response that is separate from iron homeostasis. Recent research shows that irrespective of iron levels, HFE interacts with interferon, which is the body’s initial fighter against viral infections. HFE deficiency (in mice) increased interferon and made the animals more resistant to the flu virus. [ref]
Benefit of an HFE mutation?
The negative impacts of too much iron are obvious.
Researchers hypothesize that the HFE mutations are relatively common in the population due to a survival benefit, such as women with higher iron would be less likely to die in childbirth and thus pass on the mutation to their children.
A 2021 study, though, shows an additional benefit for athletes with the HFE mutation. Competitive cyclists who have HFE mutations have faster performance times and a 17% greater V˙O2 peak. [ref] A little extra iron in the blood leading to extra oxygen capacity?
A 2020 study also found that international-level endurance athletes were almost twice as likely to carry the HFE H63D variant. The researchers think this is due to increase oxygen-binding capacity with higher iron.[ref]
The H63D mutation may decrease the risk of neurodegeneration due to the pesticide paraquat. (animal study)[ref]
Genetic Variants for Hemochromatosis:
HFE Gene Mutations:
The most common type of hemochromatosis is Type 1, or Classic, and is usually caused by variants in the HFE gene.
Check your genetic data for rs1800562 C282Y (23andMe v4, v5; AncestryDNA):
- A/A: two copies of C282Y variant, most common cause of hereditary hemochromatosis, highest ferritin levels
- A/G: one copy of C282Y, increased ferritin levels, hemochromatosis possible but less likely[ref], check to see if combined with H63D (below) – combo increases the risk of hemochromatosis
- G/G: typical
Members: Your genotype for rs1800562 is —.
Check your genetic data for rs1799945 H63D (23andMe v4, v5; AncestryDNA):
- G/G: two copies of H63D variant, can cause (usually mild) hemochromatosis, increased ferritin levels
- C/G: one copy of H63D, somewhat higher ferritin levels, can cause hemochromatosis in conjunction with one copy of C282Y (above)
- C/C: typical
Members: Your genotype for rs1799945 is —.
Check your genetic data for rs1800730 S65C (23andMe v4; AncestryDNA):
- T/T: two copies of S65C variant, can cause (usually milder) hemochromatosis, increased ferritin levels
- A/T: possibly increased ferritin levels
- A/A: typical
Members: Your genotype for rs1800730 is —.
Carrying just one copy of the HFE variant:
While most of the official hemochromatosis sites will say that you are ‘just a carrier’ for hemochromatosis with one copy of the HFE variant, in actuality, excess iron could be causing problems (just not usually to the extent of liver failure). The initial problems that come with too much iron include random joint pain, fatigue, irritability, and/or abdominal pain.
Research studies also show that carriers of HFE variants (mainly C282Y) are at a higher risk of :
- non-alcoholic fatty liver disease[ref][ref]
- metabolic syndrome[ref]
- cardiovascular disease[ref] including women with heterozygous variants[ref]
- slightly higher risk of cancer[ref][ref] including breast cancer[ref] and liver cancer[ref]
- Alzheimer’s disease, including heterozygous carriers[ref]
- musculoskeletal problems (arthritis symptoms)[ref]
- high blood pressure[ref]
- high uric acid (gout[ref]
- lung fibrosis[ref]
- cardiovascular disease in kidney disease patients[ref]
- increased lead levels[ref][ref]
Other Genes Involved in Iron Buildup:
Not everyone who is homozygous or compound heterozygous for the hemochromatosis variants will develop iron overload. Diet and lifestyle play a role in the rate at which iron accumulates. Additionally, there are other genes that play a role in ferritin levels and iron levels in the body. Some of these are listed below:
Responsible for bone morphogenetic proteins influencing hepcidin levels, which regulates iron accumulation.
Check your genetic data for rs235756 (23andMe v4; AncestryDNA):
- G/G: lower transferrin
- A/G: increased transferrin
- A/A: most common genotype; increase ferritin levels in people with HFE variants[ref][ref]
Members: Your genotype for rs235756 is —.
Check your genetic data for rs3923809 (23andMe v4, v5; AncestryDNA):
- G/G: higher ferritin levels[ref]
- A/G: higher ferritin levels
- A/A: lower ferritin levels
Members: Your genotype for rs3923809 is —.
A transmembrane protease gene, Serine 6 which regulates hepcidin levels
Check your genetic data for rs855791 (23andMe v4, v5; AncestryDNA):
- G/G: higher iron stores in men with HFE variants[ref]
- A/G: higher iron stores in men with HFE variants
- A/A: lower iron stores in men
Members: Your genotype for rs855791 is —.
Rare genetic mutations causing other forms of hemochromatosis:
Hemochromatosis can also cause mutations in other iron regulatory genes. These are really rare, but the mutations can cause hemochromatosis starting at a young age.
Check your genetic data for rs121434375 ( 23andMe i5001498 v4; AncestryDNA):
- A/A: typical*
- A/T: HFE2, pathogenic for hemochromatosis type 2A[ref]
*Note: given in the forward orientation to match 23andMe or AncestryDNA data
Members: Your genotype for rs121434375 is .
Check your genetic data for rs28939076 ( 23andMe v4; AncestryDNA):
- G/G: typical
- G/T: Hemochromatosis type 4[ref]
Members: Your genotype for rs28939076 is — .
Check your genetic data for rs74315325 (23andMe i5001502 v4; AncestryDNA):
- T/T: typical*
- T/A: Hemochromatosis type 2A[ref]
Members: Your genotype for rs74315325 is .
Check your genetic data for rs74315326 (23andMe i5001503 v4; AncestryDNA):
- T/T: typical
- C/T: hemochromatosis type 2A[ref]
Members: Your genotype for rs74315326 is .
Adult men and menopausal women who are heterozygous or homozygous for any of the HFE variants, should, in my not-a-doctor opinion, go get their serum iron, TIBC, and ferritin levels checked or ask their doctor to test them.
Ordering serum iron w/ TIBC and ferritin should give you enough information to know if you are storing too much iron. An inexpensive option, in the US, if you want to order your own test is UltaLabs. If you want your insurance or country’s health services to cover the test, talk with your doctor and explain that you carry a genetic mutation in the HFE gene.
Give Blood Regularly
If you have slightly elevated iron levels, the simplest way to manage iron levels is to give blood regularly. You will likely feel good, and you will definitely help out someone else with your blood donation. It is a win-win!
Fatty liver disease risk:
People with HFE mutations and hemochromatosis are at an increased risk of fatty liver disease (NAFLD). Talk with your doctor about tests for NAFLD.
Natural Iron Chelators and Inhibitors:
While giving blood is the most effective way to reduce iron levels, natural and pharmaceutical iron chelators can also help.[ref]
Drinking tea, coffee, or cocoa with a meal decreases iron absorption considerably.[ref]
Quercetin, a flavonoid found in fruits and vegetables, has been studied for its iron-chelating properties.[ref] A 2017 study on dendritic (immune system) cells found that quercetin “increases extracellular iron export, resulting in an overall decrease in the intracellular iron content and consequent diminished inflammatory abilities.”[ref] And a 2014 study on quercetin concluded: “Potentially, diets rich in polyphenols might be beneficial for patients groups at risk of iron loading by limiting the rate of intestinal iron absorption.” Foods high in quercetin include apples, dark cherries, tomatoes, capers, onions, and cranberries. Quercetin supplements including pure quercetin powder are also readily available.
Another flavonoid, rutin, which is a metabolite of quercetin, has also been studied for its iron chelation properties.[ref] A 2014 study in rats found: “Rutin administration to iron-overloaded rats resulted in a significant decrease in serum total iron, TIBC, Tf, TS%, ferritin levels…”[ref] Foods high in rutin include capers, black olives, buckwheat, asparagus, and berries. Rutin is also available as a supplement.
Okra: A 2015 study found that okra “dramatically decreases intracellular iron levels in H63D cells compared to untreated cells”.[ref] Time to make some gumbo.
Dietary phenols such as EGCG from green tea and grape seed extract also have shown to inhibit iron uptake in the intestinal cells.[ref]
The jury is still out on curcumin. In a double-blind, placebo-controlled, randomized, cross-over study, curcumin was found to decrease hepcidin and increase ferritin.[ref] Other studies, though, refer to curcumin as a possible iron chelator.[ref]
Taurine, in a mouse model of hemochromatosis, was found to protect against liver damage from excess iron. The study is worth reading and looking into if you are worried about iron-induced liver damage.
Cut out the alcohol:
With excess iron already stressing out your liver, don’t add to the problem by overconsumption of alcohol. The biggest risk factor for liver failure along with the C282Y mutation is the addition of alcohol. Heavy drinkers with the mutation have a 9-fold increased risk of cirrhosis.[ref]
Avoiding Iron Fortified Foods…
Research points to iron-fortified foods as a problem for those carrying the hemochromatosis genetic variants. [ref] In the US, white rice and refined wheat products are fortified with iron (e.g. bread, cereal, pasta – all have iron added).
- A Swedish study looked at the effect of iron-fortified foods on iron absorption in men with hemochromatosis.[ref] The study found that eliminating iron fortification from foods significantly reduced the iron absorbed by the men in the study. The study also found that the time needed between phlebotomy (to maintain proper iron levels in hemochromatosis patients) was increased significantly.
- A US study in 2012, though, declared that there is no evidence dietary iron content made a difference in ferritin concentration. In the study, they gave 200 people (homozygous for the HFE C282Y variant and high serum ferritin levels) surveys asking for information on the type of diet they had eaten for the last few years as well as alcohol intake. Then they compared the survey data to their serum ferritin levels to look for a correlation and drew the conclusion that iron intake doesn’t impact hemochromatosis.[ref]
Quick tip: Read the labels on packaged foods to see if they are enriched with iron. Often organic foods will not be enriched, or you can get organic flour that doesn’t have iron added to make your own bread.
Historical perspective: Leeches, Bloodletting, and Iron fortification
It hit me while researching all of this, that the bloodletters of yesteryear probably did help a small minority of people who were overloaded with iron. Using leeches to reduce iron stores was probably effective against some bacterial infections.
Fortification of iron into all wheat products in the US, which began in the 1940s, is good for children and most women of childbearing age. But it adds to the iron overload burden for some men and older women. When looking at the mandated fortification of foods with iron and folic acid, policymakers focus on the majority, at the expense of those who genetically are harmed by it.
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