Iron is an essential mineral that is fundamental to life. It is a critical component of hemoglobin, the protein in our red blood cells that carries oxygen from our lungs to the rest of our body. Iron deficiency leads to the most common type of anemia worldwide. However, just as too little iron is a problem, so is too much. In a common but often undiagnosed genetic disorder known as hereditary hemochromatosis (HH), the body loses its ability to properly regulate iron absorption, leading to a slow, silent, and toxic buildup of iron in vital organs. Often called “iron overload disease,” this condition can cause severe damage to the liver, heart, and pancreas if left untreated. The great tragedy of hemochromatosis is that its devastating complications are almost entirely preventable with early diagnosis and a surprisingly simple, highly effective treatment.

Hemochromatosis is a disorder in which the body absorbs too much iron from the diet. This excess iron has no natural way to be excreted, so it accumulates over many years in the body’s tissues, particularly in the liver, heart, pancreas, joints, and skin. Over time, this iron overload acts as a slow-acting poison, causing oxidative stress, inflammation, and eventually, organ failure.

To understand this, it is essential to first understand how the body normally handles iron. Our body’s iron balance is a masterfully regulated, one-way system. We absorb a small amount of iron from the food we eat in the small intestine, just enough to replace what we lose daily through shedding skin and other cells. The master regulator of this process is a hormone called hepcidin, which is produced by the liver.

• A helpful analogy is to think of your body’s iron absorption like a security guard (hepcidin) at the entrance of a very exclusive club. The guard’s job is to maintain a perfect head-count inside. They only let in a new person (an iron atom) when another person leaves.
• In hereditary hemochromatosis, the security guard has effectively walked off the job. The “gate” controlling iron absorption is stuck open. The body begins to absorb three to four times more iron than it needs, every single day.
• With no way to get rid of this excess, the iron begins to pile up in the “club,” first being stored in the liver. When the liver becomes overwhelmed, the iron spills into the bloodstream and deposits in other organs, where it causes toxic damage.

While the term “hemochromatosis” can refer to any state of iron overload, it is important to distinguish between the two main types:

• Primary Hemochromatosis: This is the inherited, genetic form of the disease, most commonly caused by mutations in the HFE gene. This will be the focus of this article.
• Secondary Hemochromatosis: This refers to iron overload that is a consequence of another disease or condition, such as certain types of anemia (like thalassemia) that require frequent blood transfusions, or chronic liver disease.

In my experience, many patients go undiagnosed for years because early symptoms are vague. But catching it early can prevent serious complications like liver cirrhosis or diabetes.

The most common form of hereditary hemochromatosis is caused by a mutation in the HFE gene. The HFE gene contains the instructions for making a protein that plays a crucial role in sensing the body’s iron levels. This protein helps regulate the production of the master iron hormone, hepcidin.

When the HFE gene is mutated, this sensing mechanism is broken. The liver does not get the correct signal that the body’s iron stores are full. As a result, it fails to produce enough hepcidin. Without the hepcidin “gatekeeper” to restrict absorption, the small intestine continues to absorb large amounts of iron from the diet every day, regardless of how much iron is already stored in the body.

There are two main mutations in the HFE gene that are responsible for the vast majority of cases:

• C282Y
• H63D

The specific combination of these mutations determines a person’s risk of developing a clinical iron overload.

I’ve often seen hereditary hemochromatosis in patients who had no idea it ran in their family, until they presented with unexplained fatigue or elevated liver enzymes.

HFE-related hereditary hemochromatosis is one of the most common genetic disorders in people of Northern European descent, but it affects all ethnic groups.  It is an inherited condition passed down through families in an autosomal recessive pattern.

• This means that for a person to be at high risk for the disease, they must inherit two copies of the mutated HFE gene, one from their mother and one from their father.
• Parents are almost always unaffected carriers. A carrier has one normal copy of the gene and one mutated copy. They do not typically develop iron overload themselves but can pass the faulty gene on to their children.

When two carriers of an HFE gene mutation have a child, there are three possible outcomes for each pregnancy:

• There is a 25% chance that the child will inherit two mutated genes and will be at high risk for developing hemochromatosis.
• There is a 50% chance that the child will inherit one mutated gene and one normal gene, and will be an unaffected carrier like the parents.
• There is a 25% chance that the child will inherit two normal genes and will be neither affected nor a carrier.

Because both parents must carry the same faulty gene, the chances of having a child with an autosomal recessive condition like hemochromatosis are higher in communities where marriage between close relatives is a common cultural practice.

I’ve seen cases where hemochromatosis only came to light during routine screening in siblings of diagnosed patients. Genetic testing can be a lifesaver in families at risk.

One of the most insidious aspects of hemochromatosis is that it is a “silent” disease for many years. The body is very efficient at storing the excess iron, and symptoms often do not appear until middle age, typically after age 40 in men and after age 50 or menopause in women (as women lose iron regularly through menstruation and childbirth). By the time symptoms appear, significant organ damage may have already occurred.

The early symptoms are often vague and non-specific and can include:

• Chronic, unexplained fatigue and weakness.
• Joint pain (arthralgia), especially in the knuckles of the index and middle fingers.

As the iron overload progresses and organ damage begins, more specific signs and symptoms develop:

• Liver Damage: The liver is the primary storage site for iron. Chronic overload can lead to an enlarged liver, abnormal liver function tests, and eventually cirrhosis (severe, irreversible scarring). Cirrhosis significantly increases the risk of developing liver cancer.
• “Bronze Diabetes”: Diabetes from iron damage to the pancreas, combined with skin darkening.
• Skin Hyperpigmentation: A bronze or grayish metallic hue.
• Heart Problems: Arrhythmias, congestive heart failure.
• Endocrine Issues: Hypogonadism (loss of libido, erectile dysfunction), hypothyroidism.

Clinically, joint pain in the knuckles or unexplained fatigue in someone over 40 often makes me think about testing for iron overload, even before organ damage shows up.

Diagnosis starts with blood tests, followed by genetic testing and imaging or biopsy if needed.

• Iron Studies: This panel of blood tests is the key to initial screening.
  • Transferrin Saturation (TSAT): This is the best initial screening test. It measures the percentage of the iron-transporting protein (transferrin) that is saturated with iron. In hemochromatosis, the TSAT will be abnormally high (typically over 45%).
  • Serum Ferritin: This test measures the level of ferritin, a protein that reflects the body’s total iron stores. In hemochromatosis, the ferritin level will be very high.
• Genetic Testing: If the iron studies are high, a doctor will order a blood test to check for the common mutations in the HFE gene. The presence of two C282Y mutations (C282Y homozygosity) in a patient with evidence of iron overload confirms the diagnosis of HFE-related hemochromatosis.
• Assessing Organ Damage: Once the diagnosis is confirmed, further tests are done to see if the iron overload has caused any organ damage. This can include liver function tests and imaging studies. A specialized liver MRI can now accurately measure liver iron levels, often replacing the need for an invasive liver biopsy.

I always tell patients: high ferritin doesn’t always mean iron overload. That’s why transferrin saturation and genetic tests are key to making the right call.

The primary goal of treatment is to reduce iron levels and prevent organ damage. The treatment for hereditary hemochromatosis is remarkably simple, safe, and effective.

1. Therapeutic Phlebotomy

The cornerstone and gold standard of treatment is therapeutic phlebotomy. This is just regular, scheduled blood removal from the body.

• The Process: The procedure is identical to donating blood. A unit of blood (about 450-500 mL) is removed from a vein in the arm. This forces the body to use the iron stored in its organs to make new red blood cells.
• Initial Phase: In the beginning, phlebotomy is performed frequently, often once or twice a week, to “de-iron” the body. This phase can last months to over a year.
• Maintenance Phase: Once iron levels are normal, phlebotomy is done less often (e.g., every 2-4 months) for the rest of their life to keep iron levels in check.

2. Chelation Therapy

For the small number of patients who cannot tolerate phlebotomy (for example, due to severe anemia or heart problems), chelation therapy is an option. This involves medications that bind to iron and allow it to be excreted in the urine or stool.

3. Dietary Management

While phlebotomy is the main treatment, some dietary modifications are recommended:

• Avoid Iron and Vitamin C Supplements: Patients should not take any vitamin or mineral supplements containing iron. Vitamin C increases iron absorption from food, so high-dose supplements should also be avoided.
• Limit Alcohol Consumption: Alcohol is toxic to the liver and can accelerate the progression of liver damage in people with iron overload.
• Avoid Raw Shellfish: People with hemochromatosis are more susceptible to infection with a specific bacterium, Vibrio vulnificus, which is found in raw seafood.

Phlebotomy may sound intense, but I’ve had many patients say they feel better just weeks into treatment, less tired, more energetic, and relieved to know their organs are protected.

Hereditary hemochromatosis is one of the most common genetic disorders, yet it remains one of the most underdiagnosed. Its power to cause devastating damage to the liver, heart, and pancreas is hidden behind years of silent iron accumulation. The vague early symptoms of fatigue and joint pain are often dismissed until irreversible organ damage has occurred. This is the tragedy of hemochromatosis, because it is an almost entirely preventable disease. Simple blood tests can easily detect the iron overload. The treatment, regular blood removal, is simple and highly effective. If diagnosed and treated early, before organ damage occurs, a person with hemochromatosis can expect to live a completely normal, healthy lifespan.

1. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). (2021). Hemochromatosis. Retrieved from https://www.niddk.nih.gov/health-information/liver-disease/hemochromatosis
2. American Liver Foundation. (n.d.). Hemochromatosis. Retrieved from https://liverfoundation.org/liver-diseases/hemochromatosis/
3. Iron Disorders Institute. (n.d.). Hemochromatosis. Retrieved from https://www.irondisorders.org/hemochromatosis