What is hereditary hemochromatosis? Dr. Sid Barritt discusses this disease with Dr. Ron Falk. This genetic condition causes excess iron to deposit in different parts of the body. They talk about the symptoms and how one can be tested, and the treatment for hereditary hemochromatosis. Dr. Barritt is an Associate Professor of Medicine in the Division of Gastroenterology and Hepatology.
“One of the challenges with hereditary hemochromatosis is this is a population of patients who will frequently require phlebotomy or blood draws to reduce their iron.”
– Dr. Sid Barritt
Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina. This is our series where we discuss different genetic diseases with physicians who treat patients with these conditions. Today, we will talk about hereditary hemochromatosis.
We welcome Dr. Sid Barritt, an Associate Professor of Medicine in our Division of Gastroenterology and Hepatology. Dr. Barritt specializes in liver disease, in particular non-alcoholic fatty liver disease. He sees patients who have hemochromatosis, which impacts the liver, and that will be the primary focus of our discussion today. Welcome, Dr. Barritt.
Sid Barritt, MD: Thank you.
Excessive iron deposition
Falk: What is hereditary hemochromatosis? What do those words mean?
Barritt: Hereditary hemochromatosis is a genetic disorder that predisposes to excessive iron deposition in the body. The body becomes efficient in absorbing iron, but without a great way of getting rid of excess iron, iron will then deposit in solid organs, particularly in the liver.
Falk: Now, where do we get iron from in the first place?
Barritt: Iron comes into the body via our diet—dietary iron: meat, leafy green vegetables, things like that.
Falk: One can lose iron. Women lose iron during menstrual periods. How else can you lose iron?
Barritt: Well, that’s really about it. Blood loss is about the only way to lose iron. Blood loss, GI blood loss, menstrual cycle—that’s the main way that the body disposes of iron. Iron is also formed into red blood cells, but there’s only a certain amount of red blood cells the body will make, and the rest of the excess iron is deposited elsewhere.
Falk: The goal, then, is to ingest enough iron, and have that iron make it so you have plenty enough of normal red blood cells that deliver oxygen to the body, and extra iron is handled by the liver and gotten rid of, under normal circumstances.
Barritt: Under normal circumstances, yes. Under normal circumstances, the body will only absorb but so much iron, but in the situation of hereditary hemochromatosis, the body has become perhaps too efficient at absorbing iron. So, we’ll extract extra iron out of our normal dietary intake, and then the body has nothing to do with the extra iron that it’s absorbed, and it’s deposited in the liver, the heart, the pancreas, and other places.
Falk: In hereditary hemochromatosis, how does the bowel absorb more iron?
Barritt:There are a variety of genetic mutations that take place. The most common is the HFE, hereditary hemochromatosis mutation. What happens, is through this mutation, the body will absorb more iron, deposit this iron into enterocytes, or cells within the intestinal lining, and eventually this iron stores are transferred to other areas within the body, particularly the liver, in some cases the heart and the pancreas as well, too.
Symptoms of hemochromatosis
Falk: What are the symptoms that patients with hemochromatosis actually face?
Barritt: Many patients with hemochromatosis are actually asymptomatic for a long period of time.
Falk: In other words, they don’t know they have it.
Barritt: They don’t know they have it at all. Once patients start to develop symptomatic iron overload, it can manifest depending on which organs are most affected. In some situations, patients will complain of fatigue, especially if there is excess iron overload in the heart, creating some degree of heart failure. If patients have excess iron overload in the joints, they can have arthritis. Excess iron overload in the liver can ultimately lead to scar tissue in the liver and even cirrhosis of the liver. The symptoms of cirrhosis of the liver are wide and varied and can be as mild as fatigue, but then ultimately lead to symptoms of end-stage liver disease like abdominal swelling, leg swelling, jaundice, et cetera.
Falk: And the goal is to avoid that at all costs.
Barritt: The goal is to identify this long before the symptoms occur and treat it.
Falk: Are there skin changes?
Barritt: Historically, hemochromatosis was known as “bronze diabetes.”
Iron can deposit in a variety of different places—like we mentioned before, the liver, the heart, the pancreas. Iron deposition in the pancreas can lead to pancreatic dysfunction and diabetes. One other place where iron can get deposited is in the skin. Patients will get a tan to bronze discoloration of the skin, leading to this bronzing phenomenon. Early on, “bronze diabetes” was how hemochromatosis was initially recognized.
Hemochromatosis inheritance & testing
Falk: How is hemochromatosis inherited? What is the pattern of inheritance?
Barritt: The pattern of inheritance is one that’s autosomal recessive, meaning that two parents have to be carriers of the mutation, and genetic disorders that are inherited in an autosomal recessive pattern mean that two parent carriers have a twenty-five percent chance of giving one of their offspring both abnormal genes, so they are at risk of developing disease.
Falk: How do you test for that?
Barritt: We can test for it, first by looking for excess iron. Because this disease process is relatively rare, we don’t go around testing genetics in everybody, but usually because of symptoms or other routine testing that’s done at a primary care level, a patient might have their iron stores tested.
The main test that’s done is a ferritin. Ferritin is a measure of iron stores within the body. This is also paired with a percent saturation test, which is a measure of how efficient the body is at absorbing iron. So, if the ferritin is elevated, and the percent saturation for iron is elevated, then further testing can be done to look for hereditary hemochromatosis.
Falk: Iron, which is abbreviated from the periodic table as “Fe,”—you could order, as a clinician, iron, which would be, if you’re looking on the test result it could say “Fe” or “iron.”
Barritt: Serum iron.
Falk: That would be one test. That’s not something you’re looking at—you’re looking at how well that iron is being bound.
Falk: What would you look for there, if you’re looking on “MyChart” looking for that number?
Barritt: There’s an iron panel that can be sent off, that includes the serum iron level, and something called the total iron binding capacity, often abbreviated as TIBC. From this, the percent saturation—how much iron is actually bound within the blood. That normally is less than fifty percent. The body under normal circumstances can only absorb about fifty percent of our dietary iron, or even less, in many cases. Under the circumstances of hereditary hemochromatosis, that percent saturation becomes higher.
Falk: What does it go to?
Barritt: It goes up to a hundred percent, but the diagnostic criteria are above fifty percent. Very frequently, somebody with hereditary hemochromatosis, we’ll see percent saturations of seventy, eighty, ninety, ninety-nine percent.
Falk: And the ferritin, what should that be?
Barritt: The ferritin has a normal range between fifty and one-hundred fifty. Depending on the lab, the upper limit may be in the two-hundred range. We diagnose excessive ferritin when that value gets above three hundred. Many patients with hereditary hemochromatosis, that level can be in the thousands.
Falk: So, if you’re looking at the labs, and you see somebody with a percent saturation that’s over fifty percent, and you’re seeing somebody with a ferritin that’s in the high hundreds or in the thousands, that’s a tipoff that there’s a problem.
Barritt: That’s an excellent tipoff that there’s a problem, and that’s a great starting point for the diagnosis of hereditary hemochromatosis.
Falk: What happens then?
Barritt: From there, we do genetic testing. The most common cause of hereditary hemochromatosis is from mutations in the HFE gene. We can send off testing for the most common genetic mutations that predispose people to excessive iron overload. Those are mutations in the HFE gene. The two most common ones that we can test for in the US are the C282Y mutation and the H63D mutation. What those letters and numbers mean are substitutions of one amino acid to another amino acid, at a certain locus on the protein that the gene encodes for.
This is the most common genetic mutation in the Caucasian population. About one in ten people are carriers for this HFE mutation, but only about one in two hundred have two copies of the mutation that puts them at risk of symptomatic disease, but because hereditary hemochromatosis is perhaps a little bit more complicated than we fully understand at this point, only about ten percent of people with both copies of the abnormal gene will manifest symptomatic, clinical iron overload.
Falk: If you knew your parent had hemochromatosis, would you as a child of that parent want genetic testing?
Barritt: Yes. I think that’s a reasonable thing to do. One of the challenges with modern medicine is we get a lot of information and we don’t know exactly how to use it.
If I had a young adult come to me and say, “I know both of my parents are carriers,” or “I know that one of my parents has hereditary hemochromatosis,”we could check that patient’s genotype, but just because they have the genetic predisposition doesn’t necessarily mean that they will develop symptomatic disease. In this situation, checking iron stores, seeing what their ferritin is, seeing what their percent saturation is, and if both are normal or low, taking a watchful waiting approach would be appropriate.
Reasons for a liver biopsy
Falk: Now sometimes you do a liver biopsy.
Barritt: That’s correct.
Falk: What are the reasons you would do that?
Barritt: There are two reasons for a liver biopsy. The indications for a liver biopsy are anyone with a ferritin greater than a thousand, or anybody with hereditary hemochromatosis over the age of fifty. We know that either of those two risk factors predisposes patients to greater scar tissue in the liver, if not cirrhosis of the liver. If we’re able to identify cirrhosis in the liver, then we will treat those patients somewhat differently in terms of different preventive therapies for the complications of cirrhosis.
Falk: What would that be?
Barritt: Well, first we want to exclude something called varices, so if somebody has cirrhosis of the liver, they’re at risk of bleeding from abnormal blood vessels in the stomach and esophagus. We can do testing to look for that. But even more importantly in the situation of hereditary hemochromatosis, these patients are at risk for liver cancer. We would start screening mechanisms for liver cancer with the idea of catching it early while it’s still curable.
Falk: It’s also useful to tell a patient, “Wait a minute. You’re developing scarring in your liver and protect your liver from other potential toxins.”
Barritt: Namely alcohol in this situation. There is an interplay between alcohol and iron overload, again, that we don’t fully understand. As I mentioned previously, only about ten percent of patients with the genetic predisposition for iron overload actually develop symptomatic disease. When we add alcohol to the mix, these patients are much more likely to develop advanced liver disease and cirrhosis of the liver.
Falk: Because alcoholic liver disease is pretty common.
Barritt: Alcoholic liver disease is very common, probably the most common liver disease that is out there. I wouldn’t say it’s the most common liver disease that we see, because many people who suffer from alcohol use disorders don’t come to the physician. Again, if we’re talking about a common genetic predisposition, and a common societal issue, when these two intersect, we see them together quite frequently.
Falk: I presume that fatty liver is an additional risk factor?
Barritt: Fatty liver is an additional risk factor for cirrhosis of the liver, but I can’t say that fatty liver predisposes somebody to hereditary hemochromatosis. These are two common issues.
Falk: But is there an interplay in the same way as there is with alcoholic liver disease?
Barritt: Fatty liver is relatively new on the scene in terms of it becoming a very common liver-related diagnosis. Iron may be part of the two-hit hypothesis that causes fatty liver disease to advance. We can see something called secondary iron overload in fatty liver disease just because of the chronic inflammation going on in the liver, patients can get extra iron in the liver without having a genetic predisposition for it. But, anytime you’ve got multiple insults to the liver—whether it’s fatty liver disease, whether it’s alcohol, whether it’s iron, all of these different problems can conspire to advance scar tissue and predispose somebody to cirrhosis.
Falk: In other words, if somebody has fatty liver disease because of obesity, for example, the presence of iron on a liver biopsy does not necessarily indicate that the person has hereditary hemochromatosis.
Barritt: That’s correct. It’s a separable issue. We see, in any chronic liver disease, something we call secondary iron overload. A big part of how we distinguish between a primary overload process like hereditary hemochromatosis and secondary iron overload is where we see the iron. So, in a primary iron overload process like hereditary hemochromatosis, iron gets deposited within the hepatocytes, the normal liver cells. In secondary iron overload, we see the iron deposition in other cells within the liver—white blood cells called macrophages, other places within the liver, so that helps us distinguish between primary and secondary iron overload.
Treating hereditary hemochromatosis
Falk: What, then, is the treatment for hereditary hemochromatosis?
Barritt:The treatment is actually quite simple: it’s phlebotomy. If the body loses blood—
Falk: Like bleeding in days of old.
Barritt: Right. We don’t employ leeches or cupping, or anything like that, but we do send people to the lab to have blood drawn. One of the challenges with hereditary hemochromatosis is this is a population of patients who will frequently require phlebotomy or blood draws to reduce their iron. This would seem to be a great population who could go and donate blood for altruistic reasons. Life is never quite that simple, so these patients often are excluded from donating blood, because some of their liver enzymes may be abnormal, and that is often the first screening tests that blood banks and other places employ to exclude donors—to exclude other liver-related problems like viral hepatitis.
Falk: If you get repetitive phlebotomies, how does that make the patient feel?
Barritt: It can make the patient feel normal. Most of the symptoms of hereditary hemochromatosis can be reversed with iron depletion in phlebotomy, especially if we start this early, before a patient is overly symptomatic. One of the unfortunate symptoms that can be most challenging to reverse is the arthritis that comes along with severe cases of iron overload. So, when I’m discussing therapy with a patient I want to make sure to set realistic expectations. We can reverse inflammation in the liver. We can improve diabetes, but improving the arthritis is often far more difficult.
Falk: What I’m gathering, then, is early detection, protecting one’s liver from alcohol, leading a healthy life, trying to make sure that one is phlebotomized or has blood removed on some regular basis are all part of that therapeutic plan.
Barritt: Absolutely. What I like to tell patients is what’s good for their heart is good for their liver. So, maintaining a healthy weight. Alcohol use in moderation, if at all. And getting their iron down to normal levels—these are all pieces of long-term success. If we can appropriately iron-deplete a patient, then hemochromatosis becomes sort of a “back-burner diagnosis,” so to speak. Patients can expect a normal life expectancy, if it’s caught early and there are no long-term changes to the liver, to the heart, the pancreas, et cetera.
Other forms of iron overload
Falk: Are there other forms of iron overload?
Barritt: Yes, there are other forms of iron overload. Broadly, any hereditary iron overload is referred to as hemochromatosis. The most common form of hereditary hemochromatosis is this HFE hemochromatosis that we were talking about.
There are other mutations that impact iron metabolism that can cause use iron overload, and those can be mutations in the transferrin receptor. That usually manifests a little bit earlier, and can affect men and women, it can affect any race, and these patients wind up developing disease in their thirties to forties, whereas in HFE hemochromatosis, patients are usually older than fifty and postmenopausal when they develop disease.
There’s a juvenile mutation where children can develop iron overload. Here we principally see cardiac manifestations rather than liver manifestations.
There’s a mutation in the ferroportin receptor which can impact men and women of any background or race, and manifest in age ten all the way up to age eighty, and this is really principally affected by increases in dietary iron. One of the most common manifestations that we see in the ferroportin receptor mutation is something called African iron overload where traditional beers are brewed in iron-laden drums. Patients get excessive iron intake there, and if they have the mutation they can develop symptomatic iron overload in that mutation.
Falk: So, the therapy there would be to avoid drinking beer made from an iron drum.
Barritt: Correct, so avoid excessive dietary iron in all of its forms.
More information about hemochromatosis
Falk: Where would somebody learn more about hemochromatosis if they went online? What’s a reliable place to visit?
Barritt: Hemochromatosis.org is a reasonable place to visit. I caution broadly against too much Internet research, because the Internet is a really variable resource—some good, some bad, some indifferent. Hemochromatosis.org seems to be reasonable. Probably the best source is your primary care physician. Starting there, and if there is concern for symptomatic iron overload, referral to a specialist, whether that be a gastroenterologist, a liver specialist, or a hematologist.
Falk: Thank you so much, Dr. Barritt, for visiting with us today.
Barritt: Thank you for having me.
Falk: Thanks so much to our listeners for tuning in. Next time, we will be talking with Dr. Manish Saha about thrombotic microangiopathy. You can subscribe to the Chair’s Corner on iTunes, SoundCloud, or like us on FaceBook. Thanks so much for listening.
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