Iron Overload

How the body handles iron

The body needs iron to make hemoglobin, which carries oxygen in red blood cells. It controls iron mainly by adjusting how much is absorbed from food, using a hormone called hepcidin made in the liver. Small amounts are lost through skin and gut shedding and bleeding, but there is no active excretion route. When absorption is too high, or iron is added through transfusions, it accumulates.

Causes

Primary (hereditary) iron overload

• Hereditary hemochromatosis: most often caused by two copies of the C282Y variant in the HFE gene. It is one of the most common genetic conditions in people of Northern European descent. Not everyone with the gene variants develops significant iron overload.
• Rarer genetic forms: juvenile hemochromatosis and others affecting hepcidin, transferrin receptor 2 or ferroportin.

Secondary iron overload

• Repeated blood transfusions: each unit of red blood cells contains about 200 to 250 mg of iron. People who need regular transfusions, such as those with thalassemia, sickle cell disease or myelodysplastic syndromes, build up iron quickly.
• Ineffective red cell production: conditions such as thalassemia increase iron absorption even without transfusions.
• Chronic liver disease: alcohol-related liver disease, hepatitis C and fatty liver disease can cause mild iron accumulation.
• Excess iron intake: long-term high-dose iron supplements or iron injections when not needed. Rarely, the absorption of iron from traditional drinks brewed in iron pots.

Symptoms

Many people have no symptoms for years. Symptoms often appear after age 40 in men and after menopause in women, because menstruation and pregnancy remove iron.

• Tiredness and weakness
• Joint pain, especially in the knuckles of the index and middle fingers, and in the hips and knees
• Pain in the upper right belly
• Loss of sex drive, erectile dysfunction, irregular or absent periods
• Darkening or bronze or gray tint of the skin
• Memory fog and low mood
• Palpitations or breathlessness

Complications

• Liver: enlargement, fibrosis, cirrhosis and liver cancer
• Pancreas: diabetes ("bronze diabetes")
• Heart: cardiomyopathy, heart failure and arrhythmias, a major cause of death in transfusion-dependent people
• Hormone glands: low testosterone and other hormone deficiencies, especially with transfusion overload
• Joints: arthritis, including calcium pyrophosphate deposition
• Bones: osteoporosis
• Infections: higher risk of infection with iron-loving bacteria such as Vibrio vulnificus from raw shellfish

Diagnosis

• Transferrin saturation: the percentage of iron-carrying protein filled with iron. Above about 45 percent suggests iron overload.
• Serum ferritin: reflects stored iron. Ferritin is also raised by inflammation, infection, alcohol, fatty liver and other causes, so it must be interpreted with transferrin saturation.
• HFE genetic testing when transferrin saturation and ferritin are raised.
• Liver tests and assessment for fibrosis, including elastography. A ferritin above about 1,000 micrograms per liter raises the risk of cirrhosis.
• MRI (T2-star) of the liver and heart: measures iron content without a biopsy, especially for transfusional overload.
• Liver biopsy: now rarely needed.
• Screening of relatives: first-degree relatives of people with hemochromatosis should be tested.

Treatment

Therapeutic phlebotomy (blood removal)

For hereditary hemochromatosis, about 500 mL of blood (one unit) is removed, initially weekly or as tolerated, until ferritin falls to a target range (commonly about 50 to 100 micrograms per liter). Maintenance phlebotomy is then done a few times a year. It is safe, effective and inexpensive. In some places the blood can be donated.

Iron chelation therapy

For people with anemia who cannot have phlebotomy, such as those with thalassemia, medicines bind iron so it can be excreted:

• Deferoxamine, given by infusion under the skin
• Deferasirox, a tablet
• Deferiprone, a tablet or liquid

These need regular monitoring for side effects.

Lifestyle measures

• Avoid iron supplements and multivitamins with iron.
• Avoid vitamin C supplements, which increase iron absorption (vitamin C from food is fine).
• Limit alcohol, and avoid it entirely with liver damage.
• Do not eat raw oysters or shellfish.
• No strict low-iron diet is usually necessary when phlebotomy is used.

Outlook

When iron overload is diagnosed and treated before cirrhosis or diabetes develops, life expectancy is normal. Treatment can improve tiredness, skin color, heart function and liver tests, though established cirrhosis, diabetes and arthritis may not fully reverse. People with cirrhosis need regular liver cancer screening.

Frequently asked questions

What are the symptoms of iron overload?

Early iron overload often causes no symptoms. Later symptoms include tiredness, joint pain (especially in the knuckles), upper belly pain, low sex drive, darkened skin and memory fog. Untreated, it can lead to liver disease, diabetes and heart problems.

What causes iron overload?

The most common cause is hereditary hemochromatosis, a genetic condition that increases iron absorption from food. Other causes include repeated blood transfusions, conditions such as thalassemia, chronic liver disease and, rarely, excessive iron supplements.

What ferritin level is too high?

Ferritin above roughly 300 micrograms per liter in men and 200 in women is considered raised, but high ferritin has many causes, including inflammation, alcohol and fatty liver. Iron overload is suggested when high ferritin is accompanied by a transferrin saturation above about 45 percent.

How is iron overload treated?

Hereditary hemochromatosis is usually treated with regular removal of blood (phlebotomy) until iron stores are normal, then occasional maintenance sessions. People who cannot have blood removed, such as those with thalassemia, are treated with iron chelation medicines.