Treatment and Disease Management

Hereditary hemochromatosis is only treated if the patient has iron overload, or an excess of iron stores. Not all patients will develop levels high enough to require treatment however; periodic testing of serum is required to monitor iron levels (Adams 2010). Levels of ferritin >1000μg/L are considered to be indicative of iron overload and signal that iron reduction therapy is required (Adams 2010).

Therapeutic phlebotomy is the primary means of reducing iron stores in hereditary hemochromatosis (Bacon 2011). Standard treatment consists of removal of one half liter of blood, which contains 200-250mg of iron one to two times per week. (Bacon 2011). Once levels of ferritin decrease to 50-100μg/L, the frequency of phlebotomies may be decreased (Adams 2010). Each patient is unique in his or her need for maintenance phlebotomy, ranging from once a month to once a year, following normalization of iron stores (Bacon 2011). Benefits to the patients include decreased cirrhosis, reduction of skin pigmentation and reported resolution of fatigue and arthritis symptoms (Adams 2010). Side effects from treatment can include hypervolemia (low blood volume) following treatment; fatigue and it can cause an increase in iron absorption (Adams 2010). Additionally hemocrit and hemoglobin measurements must be performed prior to phlebotomy (Adams 2010)

Therapeutic erythrocytapheresis (TE) is a more involved process that involves apheresis, or separation and removal of erythrocytes (red blood cells) while allowing the remaining white blood cells, plasma and small molecules to return into circulation (Rombout-Sestrienkova 2016). This mitigates hypovolemic symptoms and intolerance seen in phlebotomy (Rombout-Sestrienkova 2016). A larger amount of iron is removed per session and it takes a shorter period of time to complete treatment and has a higher amount of patient satisfaction (Rombout-Sestrienkova 2016).

Figure 1: A) A depiction of a patient undergoing therapeutic phlebotomy. B) The machine used to conduct theraputic erythrocytapheresis     Sources: A) B) 

Chelators are infrequently used for hereditary hemochromatosis due to side effects and liver toxicity (Adams 2010). However, they are used for patients who are unable to tolerate phlebotomy or erythrocytapheresis (Adams 2010). Commonly, Deferoxamine (DFO), which is injected, is used and showed similar resolution of iron stores compared to phlebotomy. DFO binds free irons stores through its carbonyl oxygen, which form interactions with free iron and is excreted through urine (Adams 2010). Another chelating agent Desferasirox (DFX) is administered orally but has not been studied as much in the case of hemochromatosis as DFO. DFX binds iron with a two to one ratio using aromatic oxygen’s to form interactions with iron, excretion occurs through stool (Adams 2010).

Figure 2: A) Desferroxamine (DFO) is an injected iron chelator, binding 1:1 and excreting through urine. B) Deferasirox (DFX) is a orally bioavailable iron chelator binding 2:1 and is excreted through stool. Made using ChemDraw (EMG)

In addition to reducing iron levels patients may also receive treatment for resulting conditions such as diabetes and arthritis (Bacon 2011). Patients are advised to limit alcohol usage as it can accelerate progression of cirrhosis (Bacon 2011). Patients are also advised to avoid supplemental vitamin C as it can increase iron absorption (Bacon 2011). While dietary modifications have been investigated they can only mitigate 2-4mg of iron per day, which is insignificant compared to the amount removed through phlebotomy (Bacon 2011).

Hereditary Hemochromatosis

History and Metabolic Context 

Molecular Basis of Disease

Conclusions and Proposals

Annotated Bibliography

10 Replies to “Treatment and Disease Management”

  1. Hi – nice work on this review! I am fascinated by the variable phenotype expression and how some people don’t develop excess iron stores while some need regular phlebotomies. I know on the next page you mention that penetrance is worth studying in regards to HFE C282Y, but is this the only mutation type with such variable expression or do other mutations show this amount of variability? I am also curious in regards to Hep C as a possible potentiator of the disease/symptoms (from your table on previous page) – is this a larger portion of the popution that experiences this? In other words, do most people with this mutation experience a precipitating infection like Hep C? Are there other possible infectious potentiators besides Hep C?

    Thanks for you work!

    1. Within the context of hemochromatosis, HFE C282Y, is the only one showing incomplete penetrance yet it is the most common mutation. However, other diseases such as Gaucher Disease, Factor V Leiden and interestingly BRCA1 mutations show incomplete penetrance as well.

      HepC is interesting as it alone can cause a rise in iron levels even in patients without hemochromatosis. However, in patients with hemochromatosis the iron overload can become more severe and increased deposition of iron stores can occur. In regards to other types of infections, while there are none I came across in the literature, I would be surprised if there were not additionally ones. Due to the role of iron in our immune response to infections, it seems likely that other types of infections may also cause increased iron overload in patients with hemochromatosis.

  2. Great Review! The information was very through and your explanation on normal iron regulation and how that is altered in hereditary hemochromatosis was comprehensive. You mentioned on the title page that symptoms for this disease can appear in juvenile and in adults based on the mutation causing the disease. Is there any correlation between a patients iron level’s and the age when the symptoms started? Do the patients, with the juvenile type, uptake iron more rapidly, and as a result more likely to need treatments such as therapeutic erythrocytapheresis?

    1. Hi zach,

      Great questions. Juvenile Hemochromatosis results from mutations in HJV and Hepcidin. These mutations are also fully penetrant so they always show phenotypically unlike in adult onset, HFE, hemochromatosis. Patients with the juvenile form typically display more severe iron overload then adults and also display more significant symptoms such as hypogonadism (loss of function in testes/ovaries), arthritis and cirrhosis, which especially when occurring at a young age can cause significant problems. I was not able to find anything about iron levels and age of diagnosis but it is an interesting question although it may be hard as most patients will undergo treatment to reduce iron stores.

  3. I really enjoyed your project Elaine! I especially loved your timeline of how the discovery of the disease progressed! You mention that people genetically homozygous for the HFE C282Y mutation either do not develop symptoms at all, or develop severe symptoms. Is there any way to prevent such a large buildup of iron just in case those genetically homozygous for the mutation suddenly develop symptoms? I’m curious about any preventative measures you may have found!

    1. Hi!
      To clarify a bit, the accumulation of iron occurs progressively in the body rather then occurring suddenly. Oftentimes, the symptoms of iron accumulation do not appear until a person is severely iron overloaded in which case they will present with severe symptoms such as cirrhosis or liver cancer. However, it is still the case that some people who are homozygotes never develop iron overload or symptoms while others do. This incomplete penetrance is not well understood and research is still underway to try to determine who is likely to develop the disease phenotype. The best prevention measures are one, to identify people with hemochromatosis genotype through genetic testing and second, to periodically monitor levels of ferritin and transferrin as a means of assessing iron status to determine if treatment is necessary.

  4. Hi Elaine, great work! I am interested in the chelating agents DFO and DFX which are sometimes used to remove excess iron from the blood. Are DFO and DFX natural products or are they synthetic? Do these agents have any adverse or unintended effects?
    Polyphenols are natural metal chelators: have they been explored as a potential therapy for iron overload?

    1. Hi Elliot, Thanks for your questions. DFO is produced by the bacteria Streptomyces pilosus but is produced as a salt for clinical use. DFX is a synthetic product. Both DFO and DFX have a lot of side effect including GI bleeds, renal and hepatic failure as well as nausea and stomach pain. These side effects are why the drugs are not used frequently to treat hemochromatosis, patient success rates are quite low. Interesting point about polyphenols, I did a bit of research and there are some epidemiological studies linking tea consumption (a great source of polyphenols) with decreased iron absorption. They appear to be a means of supplementing primary treatment methods.

  5. Hello Elaine!
    I first would like to say: your organization is incredible and the pictures are superb. I particularly enjoyed Figure 2 on the title page showing the how hepcidin interacts with ferroportin in order to regulate iron uptake. I was curious how transferrin and ferritin was tested in blood serum to diagnose the patient. What types of tests are performed which determine the concentration of these two molecules? How are these molecules isolated and then tested?
    Also, I was curious about these chelators. Do these chelators only bind to unbound unbound iron or is there a risk iron bound to other molecules would be also removed?
    Overall, fantastic work, Elaine. Your hard work and thoroughness really showed.
    Tyler Florio

    1. Thanks for your compliments Tyler!

      Both ferritin and transferrin (as well as a majority of our medical serum diagnostic testing) is done through ELISA (enzyme-linked immunosorbent assay) aka sandwich assays. A basic description of this technique can be found at; It provides an antibody based test that can quantify levels of specific proteins within the blood. Also, DFO and DFX specifically bind Fe(II) and Fe(III) found free in the blood due to their lower molecular weight as opposed to the higher weight of iron bound molecules.

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