Hereditary Hemochromatosis

Hemochromatosis. It’s a big word. And, if you add the word ‘hereditary’ before it, it ends up sounding like an even bigger term and an awfully alarming alliteration. But medical words and conditions have a way of seeming intimidating and that can scare us away and keep us from understanding important things because they’re intimidating. So we’re gonna refer to ‘hereditary hemochromatosis’ as ‘HH’, and raise some awareness about what it is, because it’s HH awareness month!

Hereditary hemochromatosis is much less intimidating to understand when we break it down. We already know what ‘hereditary’ means — it’s when something gets passed down through generations. Like last names, inheritance, genes, or everyone’s current topic of outrage — nepotism. The ‘hereditary’ part of HH indicates that it’s a genetic condition that may be passed from one generation to the next. The inheritance of HH can be ‘dominant’ or ‘recessive’. Okay, we’ve introduced two more words, but stay with me. This is the easiest thing to understand in genetics, and will make you feel super smart when you understand it. It’s actually quite simple. The next paragraph demonstrates how easy it is to understand “complicated” genetics stuff.

Remember how we’re all made of one egg and one sperm? I told you it was gonna be easy! The egg contains one half of our genetic material and the sperm contains the other half of the genetic material; combined, they make up the entire genetic material we need in order for our bodies to develop and function effectively. Still with me? Awesome! We have about 25,000 genes, each responsible for a specific job, and it’s not uncommon for us to have 1-2 genes that aren’t working like they should. Most times (and luckily), because of the fact that we have 2 copies of each genes — one copy from the egg, the second copy from the sperm — the working copy can easily do the job on its own and the non-working copy doesn’t cause us to have a genetic illness. It’s like having a back-up of sorts. Such genetic conditions, where one non-working gene in a gene-pair does NOT result in illness, are called ‘recessive conditions’. Well done on getting this far, you! The inheritance “pattern” of such recessive conditions is called ‘recessive inheritance’, and people who have one working copy and one non-working copy of a gene-pair are referred to as healthy or asymptomatic ‘carriers’. When egg/sperm is created, it contains half of our total DNA. If you were a carrier of a recessive condition, there’s an equal chance for each of your egg/sperm to either contain the working copy of the gene, or the non-working copy of the gene. That’s 50%, just like a coin toss. So for 2 individuals who are asymptomatic carriers of a non-working copy of the same gene to make a baby, their egg/sperm could either contain the working-copy of a gene or the non-working copy of the gene. Effectively here is a 50% (i.e., ½) chance that the male partner’s sperm that made up half of the baby contains his non-working copy of the gene, and a 50% (i.e., ½) chance that the female partner’s egg that also made up an equal half of the baby contains the non-working copy of the particular gene. In other words, While ½ and ½ add up to a full baby, the chance that the baby inherits both ½s containing the non-working gene copy is ½ * ½ = ¼, i.e., 25%. And, with this, you have expert level understanding of autosomal conditions. The picture below is definitely worth more than the total number of words in this paragraph. And I am, of course, lying about ‘expert’ level.

Out of the 4 types of HH — don’t be overwhelmed, we’ll get into those in just a bit — 3 are inherited in a recessive manner, and you already know what that means. The 4th type of HH is inherited in a ‘dominant’ manner. And now that you have, ahem, ‘expert level’ understanding of recessive inheritance, dominant inheritance is actually simpler to understand. For genetic conditions that are ‘dominant’, as the term suggests, one non-working copy of a gene-pair is enough to manifest the condition. In other words, if one had a single non-working copy of a gene related to a dominant condition, they would have that particular genetic condition. Such as type 4 HH. Further, as an individual with a dominant genetic condition has one copy of a non-working gene, there is a 50% (i.e., ½) that each egg/sperm they make contains this non-working copy of the gene, and can become part of the one half that makes their baby. 

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To summarize, someone who has an autosomal dominant condition has a single non-working copy of a gene pair; and each of their children have a 50% chance of inheriting it and, consequently, having the condition themselves. And now you have an ‘expert level’ understanding of dominant conditions as well. 😉

So we’ve talked about the ‘hereditary’ part of HH. Let’s get into the ‘hemochromatosis’ part. Hemochromatosis, like most medical words, sounds like a pretty complicated word. However, like most medical terms, breaking it down into the words-of-origin not only simplifies it but also even helps understand what it means. The term ‘hemochromatosis’ comes from 3 different words:

  1. hemo  (“blood”)
  2. chromat  (“color”) 
  3. osis  (“disease”), from the changing color of blood affected by the disorder.

By this point, it probably makes sense to you that Hereditary Hemochromatosis (not such a scary term now, is it?) is a genetic condition that causes the body to absorb excessive amounts of iron from the diet. Skin pigmentation can be one of the first signs of the disease, and can cause skin to become slate grey or brownish bronze in color. HH is considered an iron-overload condition, and all the extra iron is stored in the body’s tissues and organs, especially the skin, liver, heart, pancreas, and joints. Iron-excretion occurs at a constant rate and, without the ability to increase the excretion of iron, the body eventually gets overloaded with excess iron that can eventually cause damage to tissues and organs. Symptoms of HH include fatigue, pain in joints and abdomen, weight loss, and loss of sex drive. As the condition progresses, individuals may develop arthritis, liver disease (cirrhosis or cancer), diabetes, or heart abnormalities. Diabetes mellitus (aka type 2 diabetes). Diabetes can be an extremely important, yet often-overlooked, symptom of HH. Serum ferritin concentration may be examined in order to establish iron overload status, and therapeutic phlebotomy (removal of blood) is effective treatment and if an individual meets all routine criteria for blood donation, their blood can be used to save a life!

Remember we had talked about 4 types of HH? Now is when we talk about those.

  1. Type 1 is the most common form of the disorder and begins in adulthood. It is caused by disease-causing changes in the HFE gene. Men with this type of HH start to develop symptoms usually between the ages 40 and 60. Women usually develop symptoms after menopause as menstruation helps get rid of extra iron. Who would’ve ever imagined periods to be of any benefit?
  2. Type 2 is known as a juvenile-onset disorder as symptoms typically begin in childhood. It is caused by disease-causing changes in either the HJV or HAMP gene. By the age of 20 years, iron accumulation causes decreased or absent secretion of sex hormones. Females with type 2 HH usually start menstruation normally, but their periods stop after a few years. Among males with type 2 HH, delayed puberty or symptoms related to a shortage of sex hormones are common. Type 2 HH, if left untreated, can lead to potentially fatal heart disease by age 30.
  3. Type 3 HH is usually intermediate between types 1 and 2, and symptoms typically begin before 30 years of age. It is caused by disease-causing changes in the TFR2 gene.
  4. Type 4 HH, just like type 1, begins in adulthood and has a similar presentation as type 1 HH. It is caused by disease-causing changes in the SLC40A1 gene.

Genetic testing can help confirm a diagnosis that can, in turn, inform appropriate clinical management to prevent several secondary complications of HH including liver disease (hepatitis and/or cancer) and rheumatoid arthritis and inform recurrence risks. And genetic counselors can be valuable resources to families and physicians in facilitating diagnosis, management and adaptation to live with HH.

And with that, you’re now aware of the word we began with – hemochromatosis. Spread the word, and help spread awareness. Or just have ‘expert’ conversations about hemochromatosis. You never know whom you may end up helping.


About the Author

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Pooja Ramchandran is a pioneer in the field of genetic counseling in India and VP Genetic Counseling at Mapmygenome. She has been practicing clinical genetic counseling in India since graduating from Johns Hopkins University in 2008. She is a much sought-after expert in a niche profession and, being the first genetic counselor in the country with a formal degree in genetic counseling, she is committed to establishing the genetic counseling profession in India. When she is not offering her expertise as a genetic counselor, Pooja is a stand-up comedian.




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