hemochromatosisI have blogged before about hemochromatosis and the importance of checking your DNA results for the genetic variants that cause it, but I’m revisiting the topic today with updated research on the topic of iron overload. This is a personal cause for me, and getting the word out to as many people as possible is important because this is one bit of genetic information that can make a huge impact on the quality of life.

So now I’m digging deeper into studies on the genetic variants that cause hemochromatosis as well as looking into the effects of elevated iron in those who are heterozygous for the genetic variants that cause hemochromatosis.

Background: What is hemochromatosis?

“Hereditary (genetic) hemochromatosis (HHC) an inherited disorder of abnormal iron metabolism. Individuals with hereditary hemochromatosis absorb too much dietary iron. Once absorbed, the body does not have an efficient way of excreting iron excesses.  Over time, these excesses build to a condition of iron overload, which is a toxic [sic] to cells. Glands and organs, including the liver, heart, pituitary, thyroid, pancreas, synovium (joints) and bone marrow burdened with excess iron cannot function properly.  Symptoms develop and disease progresses.”  Iron Disorders Institute

The most common type of hemochromatosis is Type 1 or Classic and usually caused by variants in the HFE gene.

Check Your 23andMe results for rs1800562 (HFE C282Y).:

  • AA: most common cause of hereditary hemochromatosis, highest ferritin levels
  • AG: increased ferritin levels, check to see if compound heterozygous with rs1799945
  • GG: normal/ wild-type
Check our 23andMe results for rs1799945 (HFE H63D).:

  • GG: can cause (usually milder) hemochromatosis, increased ferritin levels
  • CG: somewhat higher ferritin levels, check to see if compound heterozygous with rs1800562
  • CC: normal / wild-type
Check our 23andMe results for rs1800730 (HFE S65C).:

  • TT: can cause (usually milder) hemochromatosis, increased ferritin levels
  • AT: possibly increased ferritin levels
  • AA: normal / wild-type

Iron Buildup:

So you’ve checked your genetic data and found that you are heterozygous (one variant) for one of the HFE variants…  While most of the official word on the hemochromatosis sites will say that you are just a carrier, in actuality, it could be causing you problems, just not to the extreme extent that being homozygous for the polymorphism could cause.

Doctors and researchers seem to be focused (rightly so) on the long-term consequences such as liver failure and heart failure of extreme iron overload.  But if you know that you are building up iron, you can avoid the irritations such as random joint pain (shoulder pain from getting up off the couch, random ankle pain from walking up the stairs), fatigue, and/or abdominal pain.

Recent studies showing higher disease risk due to HFE polymorphisms:

  • increased 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] meta-study [ref] breast cancer[ref] liver[ref]
  • musculoskeletal problems (osteoarthritis like symptoms) [ref]
  • high blood pressure [ref]
  • hyperuricemia (gout) [ref]
  • lung fibrosis  [ref]
  • diabetes[ref]
  • cardiovascular disease in kidney disease patients [ref]
  • increased lead levels [ref] [ref]

The Iron Disorders Institute includes these signs and symptoms of too much iron: chronic fatigue, joint pain, abdominal pain, liver disease, diabetes, irregular heart rhythm, skin color change, hypothyroidism, enlarged spleen, elevated blood sugar and more.

What now?

Men who are heading towards middle age and women who are menopausal who are heterozygous or homozygous for any of the HFE variants, in my non-medical doctor opinion, should go get their serum iron, TIBC, and ferritin levels checked.  In the US, you can order your own labs online through places like www.walkinlab.com.  Ordering serum iron w/ TBIC and ferritin should give you enough information to know if you are storing too much iron.

If you have slightly elevated iron levels, the simplest way to manage iron levels is to give blood!  You will probably feel good, and you will definitely help out someone else with your blood donation.    If your levels are really high, do go to a doctor.  Seriously.

Natural Iron Chelators and Inhibitors:

In addition to giving blood, natural and pharmaceutical iron chelators have been used to reduce iron levels in the body.[ref]

Quercetin has been studied for its iron chelating properties. [ref]  A 2017 study on dendritic (immune system) cells found that quercetin “increase extracellular iron export, resulting in an overall decrease in the intracellular iron content and consequent diminished inflammatory abilities.” 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, a flavonoid found in fruits and vegetables,  include apples, dark cherries, tomatoes, capers, onions, and cranberries.  Quercetin supplements including pure quercetin powder are also readily available.

Another flavonoid, rutin, has also been studied for its iron chelation properties.[ref]  A 2014 study in rats found: “Rutin administration to iron-overloaded rats resulted in significant decrease in serum total iron, TIBC, Tf, TS%, ferritin levels…”   Foods high in rutin include capers, black olives, buckwheat, asparagus, and berries.  Rutin is also available as a supplement and in bulk powder.

Okra.  A 2015 study found that okra “dramatically decreases intracellular iron levels in H63D cells compared to untreated cells”.  [ref]

In addition to naturally occurring iron chelators, dietary phenols such as EGCG from green tea and grape seed extract also have been shown to inhibit iron uptake in the intestinal cells.  [ref]

Curcumin, in a double-blind, placebo-controlled, randomized, cross-over study, 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.

Iron Fortified Foods…

May -or may not- be a problem for those carrying the hemochromatosis genetic variants.

A Swedish study looked at the effect of iron-fortified foods on iron absorption in men with hemochromatosis.  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 that dietary iron content made a difference in ferritin concentration.  (I actually don’t agree with their ability to draw that conclusion based on the method of doing the study.)  Basically, 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]

A few studies have looked at the impact of the overabundance of iron on obesity. It is tempting to draw correlations between the mandated iron fortification of food in the US and the current issues facing the nation such as diabetes, heart disease, Alzheimer’s and metabolic syndrome.  (I’m sure that I could make up some nice charts showing a link.)  But while the risk for each of those diseases increases with higher ferritin levels, no one seems to be publishing studies showing that iron fortification is causing them.

The Science behind Iron Overload:

Hepcidin is the iron regulatory hormone produced by the liver. Hepcidin was discovered and named in 2000, and scientists have since figured out that it controls the regulation of iron in the body and responds to lipopolysaccharides to prevent iron-loving bacteria from reproducing rapidly.  [ref]

“Hereditary hemochromatosis is caused by deficiency of the iron-regulatory hormone hepcidin (Ganz and Nemeth, 2011). Hepcidin is a 25 amino acid peptide secreted by hepatocytes. It controls iron concentrations in extracellular fluid and blood plasma by regulating the amount of ferroportin, the sole known cellular iron exporter. Ferroportin transports absorbed, recycled or stored iron from tissues into plasma (Donovan et al., 2005). Hepcidin binding to ferroportin triggers its degradation, resulting in decreased transfer of iron to plasma and consequently hypoferremia (Nemeth et al., 2004b). During infections or in response to injection of microbial molecules, hepcidin production is greatly enhanced (Armitage et al., 2011; Rodriguez et al., 2014), stimulated by inflammatory cytokines including IL-6 (Nemeth et al., 2004a; Rodriguez et al., 2014) and possibly activin B (Besson-Fournier et al., 2012). It has been proposed that hepcidin-mediated hypoferremia functions as a host defense mechanism that evolved to restrict iron availability for pathogen growth (Drakesmith and Prentice, 2012; Ganz, 2009) but this has never been demonstrated. Hepcidin was also reported to have direct bactericidal activity in vitro (Krause et al., 2000; Park et al., 2001), but the effect is seen only at unphysiologically high concentrations.” – https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4296238/

Other Genes Involved:

Not everyone who is homozygous 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:

  • BMP2 gene: rs235756 -A allele is associated with higher ferritin levels with HFE variants (several studies) [ref] [ref]
  • BTBD9 gene: rs3923809 -G allele is associated with higher ferritin levels [ref]
  • HBS1L-MYB gene: rs4895441 – G allele protects against anemia [ref]
  • SLC40A1 gene: rs1439816 – C allele may lead to more liver damage (not in 23andME v.4 data) [ref] [ref]
  • TMPRSS6 gene:  rs855791 – G allele associated with higher iron stores in men [ref
  • SLC40A1 gene:  rs11568350 (Q248H)  — leads to higher ferritin levels (not in 23andMe data)

Rare genetic forms of hemochromatosis (mostly non-HFE):

  • Hemochromatosis type 2A: listed in 23andMe as i5001498 (T is the risk allele) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001502 (A is the risk allele) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001501 (C is the risk allele)[ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5000096 (T is the risk allele) [ref]
  • Hemochromatosis type 2A: listed in 23andMe as i5001503 (T is the risk allele) [ref]
  • Hemochromatosis type 4: rs28939076 (T is the risk allele) [ref]
  • Hemochromatosis type 4: i5006507 (T is the risk allele)[ref]
  • Hemochromatosis type 4: i5006505 (A is the risk allele)[ref]
  • Hemochromatosis type 2B: listed in 23andMe as i5003867 (T is the risk allele) [ref]
  • Hemochromatosis type 1: i5012781 (C is the risk allele) [ref]
  • Hemochromatosis type 1: i5012784 (C is the risk allele) [ref]
  • Hemochromatosis type 1: rs1800562 (A is the risk allele) [ref]

Final thoughts…

It hit me while researching all of this, that the bloodletters of yesteryear probably did some good for the minority of people who were overloaded with iron.  Leeches to reduce blood and iron stores were probably effective against bacterial infections from iron-loving bacteria.

Fortification of iron into all wheat product in the US, which began in the 1940’s, 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 forced fortification of foods with iron and folic acid, it really does seem that the policymakers are focused on the majority, at the expense of a minority who genetically are harmed by it.  Since iron can takes decades to build up in the body, it may be that we are now seeing the consequences in the baby boomer generation.

More to read:





LinD7 · April 12, 2017 at 9:05 pm

Great details! Thank you.
Curious why some of these are called: CC: normal / wild-type? If normal, why do they refer to them as ‘wild type ‘?

Have you looked into rs2280673 in the RAB6B gene? I read something there that it may play a part with iron overload/toxicity.

Thanks, again.

LinD7 · April 12, 2017 at 9:16 pm

I need a 23&me for dummies book….if possible, maybe someine can make this easy.

You list various SNPs to be mindful. For example:
Hemochromatosis type 1: rs1800562 (A is the risk allele)

So, if 23andme shows, A / G, what is G? How does one determine if the gene is normal, heterozygous or homozygous?

Thank you.

LinD7 · April 12, 2017 at 9:22 pm

Sorry about this third comment, but it might be interesting for some.


“Back in 1799, Washington’s physicians justified the removal of more than 80 ounces of his blood (2.365 liters or 40 percent of his total blood volume) over a 12-hour period in order to reduce the massive inflammation of his windpipe and constrict the blood vessels in the region. Theories of humoralism and inflammation aside, this massive blood loss — along with the accompanying dehydration, electrolyte imbalance, and viscous blood flow — could not have helped the president’s dire condition.”

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