Refractory Anemia Explained: Causes, Diagnosis, And Treatment

Anemia is a medical condition in which your blood lacks enough healthy red blood cells, resulting in low oxygen flow to your cells. Red blood cells are disc-shaped cells containing an iron-rich protein known as hemoglobin. This protein binds oxygen in your lungs and transports it throughout the body.

According to the National Heart, Lung, and Blood Institute (NHLBI), anemia affects more than three million Americans. Women and people with chronic conditions have a higher risk of becoming anemic. There are many types of anemia, including iron-refractory iron deficiency anemia. 

What is refractory anemia?

Iron-refractory iron deficiency anemia (IRIDA) is an inherited, rare form of anemia that’s unresponsive to regular treatment. It is a type of myelodysplastic syndrome (MDS), a group of disorders that occur when the bone marrow doesn't make enough healthy blood cells. 

IRIDA is resistant to oral iron supplementation but partially responsive through other ways, such as intravenously (IV). People with IRIDA have abnormally pale (hypochromic) and small (microcytic) red blood cells. 

Symptoms of refractory anemia

The symptoms of iron-refractory iron deficiency anemia differ from person to person. However, the symptoms are similar to all other iron deficiency and anemia types.

The common symptoms of anemia include:

• Pale skin

• Fatigue and weakness

• Decreased appetite

• Exercise intolerance

• Vertigo or headache

• Exertional dyspnea (shortness of breath during exercise)

Symptoms of iron deficiency are:

• Sores at the corner of the mouth (angular cheilitis)

• Restless legs syndrome or poor sleeping pattern

• Craving non-food items such as soil, paper, ice, or clay

People, especially children who are diagnosed with IRIDA, may rarely experience the following symptoms:

• Difficulty swallowing (dysphagia)

• Dry or painful mouth or swollen tongue (atrophic glossitis)

• Hair loss (alopecia)

• Spoon nails (koilonychia)

What is the cause of refractory anemia?

Iron-refractory iron deficiency anemia is a genetic condition. In this disease, there is a mutation in the gene TMPRSS6 (transmembrane serine protease 6). This gene gives instructions for making a protein known as matriptase-2.

Matriptase-2 is a protein involved in regulating hepcidin production, a protein that regulates your iron balance. When there are low iron levels in the blood, matriptase-2 sends a signal, reducing hepcidin production.

IRIDA is an autosomal recessive disorder. Both parents must have a copy of the mutated gene to pass it on to their child. This means that even healthy parents can pass it on. If one of the parents does not have a recessive copy of this gene, their child cannot inherit it.

In children with IRIDA, the TMPRSS6 gene mutation causes high levels of hepcidin, which results in a decreased ability to absorb and use iron. In addition, parents with an abnormal copy of the TMPRSS6 gene are susceptible to acquired refractory iron deficiency.¹

How is refractory anemia diagnosed?

Knowing where to start the diagnostic process can be challenging because it's a rare form of anemia. Most people's journey to IRIDA diagnosis begins with a visit to a general physician, urgent care center, or emergency room. IRIDA only becomes more apparent after specialized referrals and tests.

General iron deficiency anemia is identifiable through a complete blood count—an analysis that measures the number, size, and maturity of different blood cells within a blood volume.

If your doctor diagnoses iron deficiency anemia, they’ll want to rule out possible causes.

For doctors to distinguish IRIDA from other common forms of anemia, they will likely look for the following key features:

• Lifelong anemia (hemoglobin 6-9 g/dL)

• Relatives with an autosomal recessive inheritance pattern

• A pattern of abnormal iron use—a slow, transient, and incomplete response to IV iron

• Microcytic red blood cells with a mean corpuscular volume of 45-65 fl

• Low iron levels (transferrin saturation <5%)

• No response to oral iron supplements or failing the iron challenge

For the iron challenge, your doctor will check your iron levels with a blood test. You’ll then receive a dose of iron. 90 minutes later, your doctor will perform another blood test to check for anemia and iron levels. The levels should have risen significantly. If not, this suggests IRIDA or issues with the small bowel.

If you have most or all of these features, your physician will confirm the results by checking the blood hepcidin levels.

Complications of refractory anemia

IRIDA rarely causes long-term complications, but the condition affects some people's daily lives. Some common complications include:

• Increased risk of infections

• Lung and heart problems

• Pregnancy complications

• Restless legs syndrome

• Lethargy

Treatment of iron-refractory iron deficiency anemia

IRIDA is unresponsive to oral iron supplementation but partially responsive to iron injected intravenously (parenteral iron). You will likely make multiple hospital visits for iron injections, as a repeated iron infusion can improve iron stores, red blood cell size, and anemia.

When to seek a medical professional

Talk to your doctor if you have a high risk for anemia or you notice one or more of the following signs:

• Symptoms of hemorrhoids, gastritis, tarry or bloody stool, or colorectal cancer

• Heavy menstrual periods

• Lead exposure

• If anemia runs in the family, and you would like genetic counseling before having a child

• Persistent fatigue, rapid heart rate, pale skin, breathlessness, or other anemia symptoms

• Inadequate intake of minerals and vitamins

Women considering pregnancy should also seek medical advice, as iron deficiency anemia can cause the following adverse outcomes:

• Premature birth

• Low birth baby weight

• Infant anemia

The lowdown

Iron-refractory iron deficiency anemia (IRIDA) is a rare type of anemia that is unresponsive to oral iron supplements and partially responsive to intravenous iron. The cause is a genetic mutation of a gene known as TMPRSS6. This is inheritable when both parents have a copy of the mutated gene.

Your doctor will need to use several diagnostic tools to diagnose IRIDA correctly. The symptoms are similar to iron deficiency anemia but vary from person to person. The treatment plan includes repeated infusions of intravenous iron.

Frequently asked questions

Is refractory anemia a type of cancer?

Refractory anemia is a myelodysplastic syndrome (MDS). This group of disorders occurs due to the bone marrow's inability to produce healthy blood cells. These syndromes are considered a type of blood cancer. Doctors treat every condition classified as MDS according to bone marrow and blood cell changes.