Hemochromatosis: Iron Overload, Testing, and Treatment

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Hemochromatosis is an inherited condition in which the body absorbs more iron from food than it needs and has no natural way to get rid of the extra, so iron slowly builds up in the liver and other organs. Most people first hear the word after a routine blood test: a high ferritin level on an annual physical, an iron panel ordered for fatigue, or a liver enzyme result that prompted more lab work. This page is for adults in Arlington, Annandale, and the rest of Northern Virginia who are trying to make sense of results like that, or who just learned that a parent, brother, or sister has hemochromatosis. It explains what the condition is, why a high ferritin is often not iron overload at all, how testing works, and what treatment involves, based on the American College of Gastroenterology's clinical guideline on hereditary hemochromatosis.

This article is general education, not medical advice. It cannot tell you what your own lab results mean. That takes your full results, your history, and a physician who can put them together.

What hemochromatosis is

The body controls its iron supply at one point only: how much it absorbs from food in the upper small intestine. There is no built-in way to excrete extra iron. Outside of bleeding, including menstrual periods, and the normal shedding of cells from the gut lining and skin, iron that comes in stays in. A hormone made by the liver, called hepcidin, acts as the brake on absorption.

In hereditary hemochromatosis, that brake is too weak. The ACG guideline defines the condition as an inherited iron overload disorder caused by too little hepcidin, which lets the intestine keep absorbing iron the body does not need. Over years, the excess is stored in tissues. The guideline lists the liver, pancreas, heart, joints, and pituitary gland as the organs that can be damaged. The whole point of diagnosis, in the guideline's words, is to find people before that damage happens and remove the excess iron while the injury can still be prevented.

The HFE gene and types of hemochromatosis

Most hereditary hemochromatosis comes from changes in a gene called HFE. The ACG guideline describes four main types, and type 1, the HFE type, is by far the most common. Within it, three gene changes come up on lab reports:

• C282Y. The change that matters most. Having two copies, one from each parent, is called being a C282Y homozygote. The guideline cites a meta-analysis in which about 81 percent of people with hemochromatosis that had actually caused iron overload were C282Y homozygotes.
• H63D. Much more common, carried by roughly 20 percent of white people according to the guideline. On its own it does not cause significant iron overload. One copy of C282Y plus one copy of H63D, called compound heterozygosity, can raise iron levels, but the guideline puts the chance of clinically significant iron overload with that combination at 0.5 to 2 percent, usually only when another factor such as alcohol or hepatitis C is involved.
• S65C. Less common. The guideline describes it as a variation without clinical significance.

The guideline is clear on one point that relieves a lot of worry: people who have H63D or S65C without any C282Y, whether one copy or two, should be told they are not at increased risk of iron overload. Having a single copy of C282Y, a carrier, is not the same as having hemochromatosis either.

Types 2, 3, and 4 involve other genes. The guideline calls them very rare. Type 2, juvenile hemochromatosis, is the most severe form and shows up in younger people.

Who gets hemochromatosis

The ACG guideline describes hereditary hemochromatosis as one of the most common genetic disorders among people of northern European descent. It reports a prevalence of about 1 in 200 to 400 people in the United States, Europe, and Australia, and about 1 in 300 among non-Hispanic white Americans. Rates are highest in people of Irish and Scandinavian origin and lowest in people of African descent. In a large US study the guideline cites, two copies of C282Y were found in 0.44 percent of non-Hispanic white participants and far less often in Hispanic, African American, Pacific Islander, and Asian participants.

Having the genes is not the same as having the disease. The guideline calls the penetrance of C282Y homozygosity incomplete: many people with two copies never develop iron-related illness. It estimates that about 75 percent of men and 50 percent of women with two copies develop abnormal iron blood tests, and it cites an Australian study of more than 31,000 people in which 28.4 percent of men with two copies had iron overload-related disease, compared with 1.2 percent of women.

Women are protected for much of adult life by the iron lost through menstruation, pregnancy, and breastfeeding. The guideline notes that symptoms in men usually appear in their 40s and 50s, and in women usually after menopause.

Hemochromatosis symptoms

Hemochromatosis often causes no symptoms at all, especially early, which is why it is usually found through blood work. When symptoms do appear, the ACG guideline names fatigue and joint pain as the most common early ones. Neither is specific, which is part of why the condition is easy to miss. Later, iron in specific organs can cause:

• Liver. The liver is the organ most often affected. The guideline describes anything from abnormal liver enzymes with no symptoms, to vague pain under the right ribs, to scarring and cirrhosis.
• Joints. Arthritis that typically involves the second and third knuckles of the hands, and sometimes the wrists, elbows, shoulders, and hips.
• Pancreas. Diabetes, which the guideline reports in about 13 to 23 percent of people with hemochromatosis.
• Heart. Cardiomyopathy and rhythm problems. These are uncommon, but the guideline notes that heart disease is the second leading cause of death in hemochromatosis.
• Hormones and bones. Low sex hormone levels from iron in the pituitary gland, which can cause low libido and erectile problems in men and missed periods or early menopause in women, plus thyroid problems and osteoporosis.
• Skin. A bronze or slate gray darkening, often deeper on the face, neck, forearms, backs of the hands, and lower legs.

Shortness of breath with exertion, a racing or irregular heartbeat, or chest pain needs prompt medical attention whatever the cause. Chest pain, severe shortness of breath, or fainting is an emergency. Call 911.

Hemochromatosis and the liver

Because the liver stores the most iron, the liver is where hemochromatosis does most of its serious harm. The guideline reports that the risk of cirrhosis rises significantly once ferritin is above 1,000 ng/mL at diagnosis, and estimates the lifetime chance of cirrhosis at close to 10 percent in untreated men with hemochromatosis. Alcohol makes it worse: the guideline cites a study in which drinking more than 60 grams of alcohol a day raised the risk of cirrhosis about ninefold in people with hemochromatosis.

Once cirrhosis is present, the risk of liver cancer goes up. The guideline recommends the same liver cancer surveillance used for cirrhosis from any cause, an ultrasound with or without an alpha-fetoprotein blood test every 6 months, and it adds one important point specific to hemochromatosis: that surveillance should continue even after the extra iron has been removed, because liver cancer can develop years later. For people with hemochromatosis whose liver scarring stops short of cirrhosis, the guideline suggests against routine liver cancer surveillance. Our page on cirrhosis explains how that monitoring fits into ongoing care.

The outlook depends heavily on catching it before cirrhosis. The guideline cites research in which people with hemochromatosis without cirrhosis had the same survival as the general population, while survival in people with cirrhosis was significantly reduced.

High ferritin is usually not hemochromatosis

This is the section most people need first. Ferritin is a protein that stores iron inside cells, and a high ferritin result is common. But ferritin also rises with inflammation and liver injury from many causes, so a high number does not by itself mean the body is overloaded with iron. The ACG guideline calls ferritin an excellent predictor of advanced liver scarring in people already known to have hemochromatosis, but says it lacks specificity as a screening test, because high ferritin also occurs with:

• Fatty liver disease. The guideline says people with fatty liver frequently have high ferritin, high transferrin saturation, or both. A pattern of high ferritin with normal iron, linked to insulin resistance, has its own name: dysmetabolic iron overload syndrome. Our page on fatty liver disease covers that condition.
• Alcohol. Regular heavy drinking raises ferritin and transferrin saturation and increases iron absorption.
• Hepatitis C. The guideline reports that 30 to 40 percent of people with hepatitis C have raised iron, ferritin, and transferrin saturation. Our guide to chronic hepatitis B and C covers testing and treatment.
• Cancer and chronic inflammation. Both can raise ferritin.

The guideline states plainly that among people with high ferritin who do not have two copies of C282Y, or C282Y plus H63D, fatty liver and alcohol-related liver disease are more common explanations than hemochromatosis. A high ferritin is a reason for a careful workup, not a diagnosis. If your liver enzymes were also abnormal, our guide to elevated liver enzymes walks through the usual causes and the order in which they are checked.

Iron overload from causes other than genes is called secondary iron overload. Besides liver disease, the guideline lists inherited anemias such as thalassemia and sickle cell disease, repeated blood transfusions, and iron given by infusion. Those situations are usually managed by the team treating the underlying condition.

How hemochromatosis is tested

The ACG guideline lays out testing as a sequence, and knowing the steps makes a lab report easier to follow.

Step 1: iron studies. The starting point is a blood panel that includes serum iron, transferrin saturation, ferritin, and sometimes unsaturated iron-binding capacity. Transferrin saturation, the percentage of the blood's iron carrier that is loaded with iron, is the preferred first screening test, and the guideline notes that fasting is not required to measure it accurately. A transferrin saturation above 45 percent picks up nearly all people with two copies of C282Y. A normal ferritin, defined in the guideline as under 200 ng/mL in women before menopause or under 300 ng/mL in men and women after menopause, together with a transferrin saturation under 45 percent, rules out iron overload with a negative predictive value of 97 percent.

Step 2: HFE gene testing. If transferrin saturation is 45 percent or higher and ferritin is high, the guideline's algorithm calls for HFE gene testing. It is a blood test, and commercial labs typically report C282Y, H63D, and S65C together.

Step 3: what the gene result changes. People with two copies of C282Y move on to treatment planning. People who do not have two copies of C282Y get evaluated for other causes of abnormal iron results, including liver and blood disorders. For people with iron overload who test negative for both C282Y and H63D, the guideline suggests against further genetic testing for the rare non-HFE types in most cases, because conditions like fatty liver and alcohol-related liver disease are far more common. It reserves that testing for unusual cases, such as a young person with heart or hormone problems from iron.

Measuring liver iron and scarring. For someone with suspected iron overload who does not have two copies of C282Y, the guideline suggests a non-contrast MRI with software that estimates liver iron concentration, often called MRI T2*, as a way to measure liver iron without a needle. Liver biopsy is now used mainly to stage scarring. For a person with two copies of C282Y and a ferritin under 1,000 ng/mL, the guideline says biopsy is not needed unless there is another risk factor for cirrhosis, because fewer than 2 percent of them have advanced scarring without one. Above 1,000 ng/mL, biopsy for staging is suggested. The guideline also notes that liver stiffness scans, transient elastography, have not been validated for staging scarring in hemochromatosis.

Hemochromatosis treatment: phlebotomy

The treatment for hemochromatosis is simple in concept: remove blood, which removes the iron it carries, and the body pulls stored iron out of the organs to make new red blood cells. The ACG guideline recommends therapeutic phlebotomy, a procedure very much like donating blood, as the first-line treatment for people with two copies of C282Y or with C282Y plus H63D.

Who starts treatment. The guideline says treatment should begin for people with two copies of C282Y whose ferritin is above 300 ng/mL in men or above 200 ng/mL in women, along with a transferrin saturation of 45 percent or more. It suggests treatment even when ferritin is under 1,000 ng/mL, because a meaningful share of untreated people progress above that level over time and treatment was linked to less fatigue and better quality of life in a randomized trial. People with two copies of C282Y and a normal ferritin at diagnosis are unlikely to develop significant overload later and can be monitored with periodic liver and ferritin tests instead. For C282Y plus H63D, the guideline says other factors such as fatty liver, diabetes, and alcohol should be addressed first, before iron removal is considered.

What the schedule usually looks like. The guideline describes two phases:

• Induction. Typically weekly sessions removing about 500 milliliters of blood, roughly one standard blood donation. Hemoglobin is checked before and during treatment and kept above 11 g/dL, and ferritin is checked monthly. The goal is a ferritin of 50 to 100 ng/mL. People who do not tolerate weekly sessions can have smaller volumes or longer gaps, which lengthens the process.
• Maintenance. Once the goal is reached, sessions drop to typically 3 to 4 times a year, with the aim of keeping ferritin near 50 ng/mL.

How long the first phase lasts depends on how much iron has built up, which is why the schedule is set and adjusted by the treating physician rather than in advance.

Diet and supplements. The guideline's patient counseling advice is that people undergoing phlebotomy do not need to cut out red meat or restrict iron in food, though it notes a review suggesting a lower-iron diet may modestly reduce how much blood needs to be removed. It does advise avoiding iron supplements and vitamin C supplements, because vitamin C increases iron absorption. It is worth asking before starting any supplement, including a multivitamin.

Blood donation. The guideline says phlebotomy does not medically prevent a person with hemochromatosis from being a blood donor, and that blood removed during treatment has been used for transfusion. It also notes that there is no universal policy and blood banks differ. Anyone hoping to have treatment sessions count as donations should ask the blood center directly.

What phlebotomy improves, and what it does not

Setting expectations is part of treatment. The ACG guideline's counseling box lists what tends to get better and what usually does not:

• May improve: abnormal liver tests, heart function, fatigue, and skin darkening, which fades slowly. Studies comparing liver biopsies before and after treatment found that mild to moderate scarring can improve.
• Usually does not improve: diabetes, established joint disease, low sex hormone levels, and cirrhosis. Some people do report less joint pain after iron removal, but joint damage that is already present can progress.

That list is the strongest argument for testing family members early: the damage that does not reverse is the damage that treatment can prevent if it starts first.

Other hemochromatosis treatments

Phlebotomy is not the only option, but the guideline is specific about where the alternatives fit.

• Iron chelation. Medicines that bind iron so the body can excrete it. The guideline recommends against chelation as first-line treatment, given how well phlebotomy works and the possible liver and kidney side effects of chelation. It recommends chelation for people who cannot tolerate phlebotomy, do not respond to it, or would be harmed by it, such as people with severe anemia or heart failure.
• Erythrocytapheresis. A machine-based procedure that removes red blood cells and returns the rest of the blood. It removes more red cells per session, so fewer sessions are needed, though the guideline notes it costs more. It can be useful for people with low platelets or low blood protein.
• Acid-reducing medicines. Proton pump inhibitors reduce iron absorption, and a randomized trial cited in the guideline found people taking one needed fewer phlebotomies. The guideline still recommends against using them as the main treatment for hemochromatosis, while noting that people who already take one for another reason may need fewer sessions. Our page on long-term PPI use covers the tradeoffs of staying on these medicines.
• Liver transplant. The guideline recommends transplant for people with hemochromatosis who have decompensated cirrhosis or liver cancer. A transplant also corrects the underlying iron regulation.

Hemochromatosis in the family: who should be screened

Because hemochromatosis is inherited, a diagnosis in one person is information for the whole family. The ACG guideline recommends that family members of people diagnosed with hemochromatosis be screened, particularly first-degree relatives: parents, brothers and sisters, and children. It notes that relatives who carry two copies of C282Y often show the disease, partly because families share habits and environment as well as genes.

For children of a person with hemochromatosis, the guideline describes a practical shortcut: test the other parent. If the other parent's HFE result is normal, each child can carry at most one copy of C282Y and does not need further testing. If the other parent cannot be tested, the guideline says children do not need testing until age 18, because hemochromatosis rarely causes problems before adulthood.

The guideline does not recommend screening the general population, citing how much the gene varies across ethnic groups and how many people with the genes never become ill.

Hemochromatosis is also the opposite problem from iron deficiency. A person with low iron, especially an adult man or a woman after menopause, needs a search for slow blood loss, often from the digestive tract. Our guide to iron deficiency anemia covers that evaluation.

Questions to bring about hemochromatosis

The visit goes further when you bring every iron panel, liver test, and gene report you have, with dates. Ferritin and transferrin saturation are read as a pattern over time, and an old result can change the interpretation of a new one. Questions worth asking:

• What was my transferrin saturation, not just my ferritin?
• Could fatty liver, alcohol, inflammation, or another condition explain my ferritin?
• Do I need HFE gene testing, and if I had it, which changes did it find?
• If I have two copies of C282Y, does my ferritin level mean I need a liver biopsy or other test of scarring?
• If I need phlebotomy, where will it be done, how often, and how will we track progress?
• Which family members should be tested, and how?
• Should I stop any supplements, including multivitamins with iron or vitamin C?

Our page on what to expect at your first gastroenterologist visit covers the rest of the appointment, and our guide to when to see a gastroenterologist covers other reasons to come in.

Hemochromatosis care in Northern Virginia with GC of NoVA

Gastroenterology Center of Northern Virginia sees adults across Arlington, Annandale, and the surrounding communities who have a high ferritin on routine blood work, an abnormal iron panel, a positive HFE gene test, or a family member with hemochromatosis. Our five gastroenterologists review your lab history, look for the more common causes of high ferritin such as fatty liver and alcohol, order HFE testing when the iron studies call for it, assess the liver for scarring, and plan and monitor treatment over time. Liver care is a core part of our practice, alongside the evaluation of fatty liver, hepatitis, and abnormal liver tests.

We see patients at our Arlington office at 1715 N George Mason Drive, adjacent to VHC Health, and our Annandale office at 3299 Woodburn Road in the Woodburn Medical complex. To schedule a visit, call Arlington at (703) 522-7476 or Annandale at (703) 560-6106, or learn more at gcofnova.com.

This article is for general education and is not medical advice. Talk with a qualified gastroenterologist about your symptoms, diagnosis, and treatment options.