Transfusion Iron Overload

What is Transfusion Iron Overload?

Our body cannot actively get rid of too much iron. We absorb iron from our small intestines daily and lose it through sweat, menstrual cycles, hair and skin cell shedding, and blood cell turnover. The typical daily absorption and loss of iron is 1 mg.

People who receive blood transfusions for anemias that are not caused by iron deficiency are at risk of having too much iron in their bodies because of the transfusions. Conditions that require regular transfusions include:

* Thalassemia major
* Sickle cell disease
* Myelodysplastic syndrome
* Aplastic anemia
* Hemolytic anemia
* Refractory sideroblastic anemia

One bag of transfused blood contains roughly 200 to 250 mg of iron. Some patients need repeat transfusions, and any extra iron can build up in the liver, hormone-producing organs, heart, and other tissues causing serious illness or even death. Iron builds up and leaves different tissues at various speeds. Treatment to remove excess iron, known as iron chelation therapy, is necessary to prevent iron from reaching dangerous levels. This type of treatment, among with other strategies, has dramatically increased the lifespan of patients who are dependent on transfusions.

Liver disease has been seen as the most common side effect. Patients who have liver disease may develop a condition called cirrhosis and have a higher risk of a type of liver cancer known as hepatocellular carcinoma. Iron buildup in the heart muscle, or iron cardiomyopathy, can be the cause of death in patients with thalassemia major.

Doctors monitor patients’ iron statuses by checking levels of serum ferritin, iron, and transferrin saturation in the blood, as well as conducting heart and liver imaging tests. Starting iron-chelation therapy early can prevent severe, life-threatening consequences.

What Causes Transfusion Iron Overload?

Having too much iron in your body, otherwise known as iron overload, often happens when a person gets a lot of blood transfusions. Certain health conditions might lead to someone needing lots of transfusions, and these include:

* β-thalassemia major: a severe blood disorder
* Myelodysplastic syndrome: a group of disorders caused by poorly formed blood cells
* Sickle cell disease: a group of disorders that cause red blood cells to become misshapen and break down
* Aplastic anemia: a condition where your body stops producing enough new blood cells
* Hemolytic anemia: a group of disorders where red blood cells are destroyed faster than they can be made

Each standard unit of donated blood holds around 200 to 250 milligrams of iron. If a person gets more than 10 to 20 units through transfusions, this could lead to having too much iron in their body. Our bodies don’t have a good way of getting rid of extra iron naturally, so it’s important to carefully manage how much iron we take in and reuse.

The hormone hepcidin helps to control how much iron we absorb from food and how much gets reused. This is important as certain cells destroy old red blood cells and in doing so, recover about 25 milligrams of iron every day. This happens in a form of iron (Fe2+) that can easily react and damage proteins and DNA. To prevent this damage, our bodies convert this iron into another form (Fe3+) that doesn’t react as readily.

This harmless form of iron (Fe3+) then attaches to a protein called transferrin. When there’s more iron than transferrin can carry, the extra iron gets left behind. This left behind iron is in the more harmful form that can react and cause damage (Fe2+). This harmful iron can get into cells of the heart, liver, pancreas, and glands that move other elements like calcium and zinc. Usually, the heart, pancreas, and pituitary gland don’t collect iron unless something abnormal is happening.

The hormone hepcidin also plays a role in how much iron gets released from cells that take in iron and cells that hold onto iron for storage. When there’s too much hepcidin, it can prevent iron from moving from these cells into the bloodstream. Having too much iron or being inflamed can increase hepcidin levels, while lack of oxygen, having anemia, and needing more red blood cells can lower hepcidin. This then releases the harmful form of iron into the blood. People with issues making enough red blood cells, like those with thalassemia and aplastic anemia, tend to have higher iron levels than people who need transfusions for other reasons.

Risk Factors and Frequency for Transfusion Iron Overload

In the US, around 15,000 people with sickle cell disease and 4,500 people with myelodysplastic syndromes and other chronic anemias need regular blood transfusions. This number reaches about 100,000 worldwide. The average age for starting blood transfusions is 4 for children with thalassemia and 12 for those with sickle cell disease, whereas it’s 40 for adults with aplastic anemia and 60 for patients with myelodysplastic syndromes.

The amount of iron overload from blood transfusions varies globally, it is dependent on how early screening and preventive measures are implemented. One study showed that over half of males and females with thalassemia had delayed puberty. Another study reported that among patients with thalassemia major, one-third regularly use chelation therapy, and among all these patients, over 85% had iron overload.

• People in the West and Far East have more iron in their heart muscles than those in the Middle East.
• A study in Japan showed that of 1109 cases of iron overload, 93.1% happened after transfusions.
• Amongneath a group of Greek patients with thalassemia major who needed regular transfusions, 51% had moderate to severe iron overload, with abnormally high levels of serum ferritin, which is a marker for iron levels in the body.

Signs and Symptoms of Transfusion Iron Overload

Transfusion iron overload is a condition that requires close medical attention. Doctors need to track details such as how long the patient has been dependent on transfusions, how often they receive these procedures per year, and if they are properly following their medication routine to remove the excess iron (called chelation). This condition initially shows signs similar to anemia: fatigue, breathlessness, and pale skin. The first prominent symptom usually is delayed puberty. Other symptoms can vary based on which part of the body is affected.

The symptoms can be categorized into a few groups:

• General symptoms: weight loss, fatigue, joint pain, pale skin, and breathlessness
• Cardiac symptoms: difficulties in breathing, swelling in the lower legs, and interrupted breathing during sleep, typically due to heart failure
• Endocrine symptoms: late onset of puberty, irregular menstrual cycle, excessive urine output, strong thirst, severe hunger due to diabetes, and stunted growth, which generally stem from iron buildup in pancreas, thyroid, and pituitary gland
• Gastrointestinal symptoms: abdominal pain and bloating, vomiting blood, black stool, cognitive impairment, sleep problems, slow movement, overactive reflexes, stiff muscles, jerky muscle contractions, and flapping tremor generally caused by liver cirrhosis

Potential physical signs that doctors might observe in patients with transfusion iron overload include:

• Bronze or grey skin color
• Easy bruising
• Stunted growth
• Extreme thinness
• Delayed breast development in teenage girls
• Soft, small testes in males
• Enlarged liver
• Fluid in the abdominal cavity
• Enlarged veins around the belly button
• Swollen neck veins
• Swelling in the lower legs
• Excess fluid in the lining of the lungs

Testing for Transfusion Iron Overload

Iron overload doesn’t have a specific lab test for detection. However, a serum ferritin test, which is cost effective and widely available, can help gauge iron overload from transfusions. If you have a condition known as thalassemia and your ferritin reading is greater than 2500 ng/dL, you have an 80% increased risk of heart-related death. However, conditions like inflammation, cancer, metabolic syndrome, kidney failure, liver disease, or heavy alcohol consumption can increase ferritin levels, making a single ferritin test not entirely reliable for assessing iron overload.

Health professionals usually advise getting both serum ferritin and transferrin saturation levels tested every three months for more accurate assessment of your body’s iron level. The various recommended upper limits for ferritin in the context of iron toxicity are from 1000 ng/mL to 3000 ng/mL. However, the ferritin test is limited in that it’s not specific and can vary between individuals.

Patients with iron overload typically have high serum iron levels and low total iron-binding capacity (TIBC). However, these results depend on the method used to measure these parameters. Transferrin saturation, although easy to measure, is not a perfect method. Nevertheless, a transferrin saturation level over 50% suggests a high iron load, although this can fluctuate with inflammation.

Non-transferrin-bound iron (NTBI) and labile plasma iron (LPI) are specific markers for iron overload and can be beneficial in monitoring response to chelation therapy, a type of iron-reducing treatment. However, more studies and standardization of tests are needed before these become routine procedures.

Magnetic Resonance Imaging (MRI) is currently the best way to monitor long-term liver and heart iron levels. A cardiac T2* MRI test has improved value in forecasting heart-related risk; T2* is the time that the organ takes to lose about two-thirds of its signal. Iron concentration is inversely related to T2*; as iron concentration increases, T2* shortens. A T2* reading less than 20 milliseconds suggests an increased likelihood of impaired heart pump function (left ventricular ejection fraction or LVEF). Most guidelines recommend getting a cardiac and liver MRI annually. If there is a liver iron concentration (LIC) greater than 0.15 mg/g dry weight or there is cardiac dysfunction, an MRI every six months is advised. However, if the LIC is normal, an MRI every two years is adequate. LIC can be calculated using atomic absorption spectrophotometry on tissue obtained from a liver biopsy.

Ferritin levels in the liver can vary, and liver iron overload can be classified as mild (less than 7 mg/g dry weight), moderate (between 7 and 15 mg/g dry weight), or severe (greater than 15 mg/g dry weight).

A liver biopsy is considered the best method, especially when MRI is not available, but it’s not frequently used because of the risks involved, such as bleeding, and problems with patient compliance. The amount of iron stored in the liver indicates the total body iron stores. Typically, additional tests may be required such as free thyroxine (T4), thyroid-stimulating hormone (TSH), calcium, phosphate, 25-OH vitamin D, fasting blood sugar, hemoglobin A1c, liver function (alanine aminotransferase and aspartate aminotransferase) tests, echocardiography, and bone density testing.

Treatment Options for Transfusion Iron Overload

Vitamin C improves the body’s ability to absorb iron from food. However, you should avoid vitamin C, alcohol, and iron supplements. Doctors use a treatment called iron chelation therapy to prevent and deal with excessive iron in the body. Ideally, this therapy is started before high levels of iron have caused significant health issues. It works by removing a specific form of iron (non-transferrin-bound iron) and iron that’s stored in the liver, which are most responsive to this therapy.

The timing of when to start chelation therapy depends on when the person started needing frequent blood transfusions and the current level of damage due to excessive iron. Usually, doctors start this therapy after about 1 to 2 years of regular blood transfusions or after 15 to 20 blood transfusions. People who have very high levels of a protein that stores iron (serum ferritin), above 1000 to 1500 mcg/L, or who have high liver iron levels, or who have low levels of a specific heart measure on an MRI scan, also need this therapy. These high levels correspond to having received approximately 120 to 200 mL of transfused red blood cells/kg.

For children, the American Academy of Pediatrics recommends iron chelation therapy when the ferritin level is more than 1500 ng/mL or when liver iron is more than 7 mg/g of dry weight. The success of this therapy depends a lot on how well the person sticks to the treatment regimen. So, doctors find it useful to adjust the treatment to improve patient compliance.

Commonly used chelation therapy drugs in the United States are deferoxamine (DFO), deferiprone, and deferasirox. Doctors assess the patient’s iron levels and previous chelation rates before starting or changing the treatment.

Deferoxamine is usually the first option for treating high levels of iron resulting from blood transfusions. It’s given as a continuous drip into a vein or under the skin. This drug helps stops diabetes, heart disease, and liver cirrhosis (scarring of the liver). In the body, deferoxamine attaches to circulating and tissue iron and eliminates it in urine and bile (a digestive fluid produced by the liver).

On the other hand, deferasirox is a chelation drug that can be taken orally and removes iron stored in bile. It’s favored by many due to the once-daily dosing and lower cost. However, possible side effects such as gastrointestinal bleeding, reduced white blood cell count, liver scarring, and kidney failure may limit its use.

Both deferoxamine and deferasirox are significantly effective in reducing buildup of iron in the heart and liver. Doctors decide the dose of these iron chelation drugs based on various factors such as serum ferritin and imaging tests of the liver and heart. The aim is to maintain a serum ferritin level below 1000 mcg/L, a cardiac T2* above 20 ms, and the LIC below 3 mg/g DW. In young children, the dose of deferoxamine should not exceed 25 to 30 mg/kg to minimize the risk of side effects. Pregnant or breastfeeding patients are typically advised to avoid iron chelation therapy.

Maintenance therapy is used to prevent tissue damage from excessive iron. If someone has too much iron stored in their liver, or has high levels of serum ferritin, or a low cardiac T2* MRI value, it indicates that insufficient iron has been removed. In this case, primary treatment goal is to remove iron overload in the heart. It’s common for someone to not achieve adequate iron removal with one iron chelator. Many people will need changes to their treatment, including a higher dose, a different chelator, or a combination of chelators. In case someone needs a lot of transfusions, removing the spleen can reduce the uptake of iron from transfusions. Organ transplantation may be considered for people with severe disease.

What else can Transfusion Iron Overload be?

Some other medical conditions might present symptoms similar to iron overload caused by frequent blood transfusions. These include:

• Hemochromatosis (a condition causing your body to absorb too much iron from the food you eat)
• Cardiomyopathy (disease of the heart muscle)
• Acute inflammatory conditions (temporary severe inflammation)
• Malignancy (the presence of cancer)
• Arthritis (joint inflammation)
• Diabetes (high blood sugar)
• Hepatitis C (a viral infection causing liver inflammation)
• Human immunodeficiency virus (HIV) infection
• Dysmetabolic hyperferritinemia (a condition with high levels of ferritin, a protein that binds to iron)

What to expect with Transfusion Iron Overload

Without a particular treatment called chelation therapy, people are likely to die of heart rhythm problems or heart failure in their late childhood or early teenage years. The future health of people with iron overload, which is a condition where too much iron builds up in the body, highly depends on early diagnosis and sticking to preventive measures.

Damage to the heart and endocrine system (the system that produces the body’s hormones) are reversible with treatment, but results can vary. The introduction of preventive treatment, known as iron chelating therapy (ICT), has seen steady improvement in life quality and the lifespan of people carrying too much iron due to blood transfusions.

However, these individuals still face a higher risk of cancer, and their overall death rate is three times higher than that of people in the general population.

Possible Complications When Diagnosed with Transfusion Iron Overload

Without chelation therapy, a treatment to remove heavy metals from the body, children and teenagers are likely to experience life-threatening heart issues. A person’s prognosis when suffering with an excess of iron in their bodies largely depends on how early it’s detected and how consistent they are with precautionary measures. Heart damage and hormonal issues due to excess iron can be reversed, but results vary from person to person. Thanks to preventive iron chelation therapy (ICT), people with an overload of iron from blood transfusions have seen an improvement in their life quality and lifespan. However, these individuals still have an increased risk of cancer and a mortality rate three times higher than the general population.

The long-term complications associated with transfusion iron overload include:

• Liver cirrhosis
• Liver failure
• Heart muscle disease
• Heart rhythm problems
• Heart failure
• Diabetes
• Underactive sex glands
• Cancer
• Parathyroid gland issues
• Hidden adrenal gland deficiency
• Need for stress steroids
• Underactive thyroid gland
• Joint disease.

A typically wide and weak heart condition is the primary cause of early death in these patients.

Chelation therapy, too, has several complications. For instance, with Deferoxamine:

• Eye damage leading to night blindness or loss of visual field
• High-frequency hearing loss
• Growth and bone defects in children causing issues similar to rickets, changes in the growing parts of the bones, and spinal damage.

Thus, it is important for children to be monitored for vision and hearing loss every six months and adults every year. Regular monitoring of growth is crucial for children, particularly their sitting height compared to total height for early detection of spinal growth defects.

Deferasirox, another treatment option, may lead to:

• Nausea, vomiting, and diarrhea
• Raised liver enzymes
• Sudden kidney damage
• Changes in vision and hearing.

Patients starting on this treatment should have their kidney function checked. During the first month, this should be done weekly if the patient has additional risk factors for kidney disease. Based on the kidney function results, the dosage can be adjusted.

Lastly, for Deferiprone, potential complications include:

• A drastic reduction in white blood cells
• Raised liver enzymes
• Joint disease
• Zinc deficiency.

Close monitoring of the overall blood count is needed every week for the first year, then every two weeks thereafter. If the treatment consistently leads to liver enzymes being more than twice the normal level, it should be stopped. Given the risk of zinc deficiency, zinc supplements should be taken.

Preventing Transfusion Iron Overload

People suffering from diseases like thalassemia, aplastic anemia, sickle cell disease, and myelodysplastic syndrome often have to rely on regular blood transfusions. Each transfusion adds about 200 to 250 mg of extra iron to your body, which unfortunately, the body cannot naturally get rid of. After receiving multiple blood transfusions, the extra iron starts building up in the liver, heart, pancreas, and thyroid. This can lead to serious health conditions like cirrhosis of the liver, heart disease, failure of the heart, thyroid issues, and even delayed puberty.

Iron chelation therapy is a treatment where doctors use medications to help get rid of the extra iron from your body, which helps prevent severe health issues like cirrhosis, heart diseases, and diabetes. The medicine can be given in different ways – through an injection into the vein, a shot under the skin, or taken orally.

Doctors practicing this therapy will keep track of the total iron in your body using routine blood tests. Currently, it’s suggested to check the iron levels (serum ferritin levels) every three months and a complete iron test (serum iron panel) annually. To monitor the iron content in organs like the liver, an annual MRI scan, or tissue sample if MRI is not available, will be part of the plan. If you have heart failure and are undergoing an intensive form of this therapy, you might need an MRI scan every 3 to 6 months. Doctors will also monitor other important indicators like blood glucose, vitamin D, calcium, and thyroid levels.

Iron chelation therapy significantly improves survival chances in the long run. Doctors will discuss the benefits and risks of this therapy with you and your family, which is an important step as it helps improve your understanding of the treatment leading to better adherence to the therapy. You will be closely watched for any unwanted side effects from the medication. It’s also beneficial to limit consumption of iron-rich foods like red meat, beans, spinach, and excess vitamin C.