Overview 

You’ve probably heard that iron is crucial for your health, helping your body grow and function properly. But what happens when there is too much or too little iron? Keeping iron levels balanced is essential; not enough iron can cause anaemia, while too much iron can damage organs.

Ferroportin disease is a rare condition where a gene mutation impairs iron transport, causing iron overload. Iron chelation therapy is one of the treatment options which reduces iron levels. Common chelators used that will be discussed are deferoxamine, deferasirox, and deferiprone.¹

What is ferroportin disease (FD)?

Ferroportin disease, also known as hemochromatosis type 4 (or SLC40A1-related hereditary hemochromatosis) is defined as iron overload disorder. It causes an unusual build-up of iron in the body. The prefix ‘ferro-’ comes from the latin ferrum, meaning iron. ‘Portin’ comes from the word transporter since ferroportin transports iron.¹ 

It is inherited differently than other hereditary iron overload disorders. An example is hereditary hemochromatosis- a condition where the body absorbs too much iron from food, leading to accumulation in vital organs. This accumulation can damage the structure and function of the organs such as the heart, liver, pancreas, or joints.¹

Causes of ferroportin disease

Iron from the food we eat does not enter the bloodstream immediately. Ferroportin protein sits on cells in the intestines and moves iron out of those cells into the bloodstream. This is called absorption. The blood then carries the iron to tissues and organs. Ferroportin also removes iron from immune cells in vital organs (liver, spleen, and bone marrow).²

The SLC40A1 gene, also called the Ferroportin 1 gene or the FPN1 gene, encodes instructions to make the ferroportin protein. When changes in the gene happen, Ferroportin occurs.

Changes in the SLC40A1 gene result in an abnormal build-up of iron in the body, because of low levels of effective ferroportin.^1,2

Ferroportin is regulated through a protein called hepcidin. Hepcidin binds to ferroportin and breaks it down when there is enough iron in the body. When iron levels are low, hepcidin levels decrease, allowing ferroportin to transport iron into the blood, enabling tissues to receive iron.²

Understanding ferroportin disease and its inheritance

Researchers believe that the different ways the SLC40A1 gene changes affect ferroportin lead to the two forms of the disorder.

The disease can result from a mutation in the gene at any point in a person’s life, or can be inherited. The inheritance pattern is autosomal, meaning one copy of the defective gene is enough for it to be passed on. This means that there is a 50% chance of the child developing ferroportin disease if the parent has the defective gene.³

Symptoms of ferroportin disease

In general, ferroportin disease is classified into two main types:^4,5

• 4A: Most people with ferroportin disease experience a mild form which is characterised by high levels of ferritin and low levels of saturated transferrin. Individuals may develop mild liver damage and joint symptoms throughout their life
• 4B: A smaller group of individuals develops a rare form of ferroportin disease similar to classic hemochromatosis (also known as hemochromatosis type 1 or HFE-related). In this type, transferrin saturation is markedly elevated. People often develop symptoms such as diabetes, irregular heart rhythms, and joint pain. Liver damage is more common in this form

Diagnosis of ferroportin disease

Diagnosing ferroportin disease involves:¹

• Identifying its typical symptoms
• Taking a detailed medical history
• Performing a thorough clinical examination
• Conducting various specialised tests

A family history of affected individuals across generations strongly suggests the condition. Higher ferritin levels and low or normal levels of transferrin (in mild cases) can be seen in blood tests. Genetic testing for changes in the SLC40A1 gene is required to confirm the diagnosis.¹

Treatment options for ferroportin disease

Treatment focuses on managing the symptoms, which vary across individuals depending on the type of disease and severity:¹

• The type that is similar to classic hemochromatosis is usually treated with regular phlebotomy (removal of blood via a vein)
• On the other hand, the milder form may not require treatment due to the risk of complications caused by phlebotomy, e.g., anaemia
• Additional treatments usually target symptom management and offer supportive care
• Iron chelation therapy is an effective way to manage iron overload and reduce the negative effects of it. Chelation can help prevent the harmful effects of iron accumulation by reducing labile plasma iron (LPI) and non-transferrin-bound iron⁶

Iron chelation therapy

The goal of chelation therapy is to manage iron levels in the body, keeping them within a safe range.^6,7

Iron chelators are developed in a way that allows them to remove excess iron by attaching to it, forming a complex. This is then excreted via urine or feces.^6,7

Deferoxamine (DFO)

Known as desferal, is the first approved drug for long-term iron overload situations. It lowers serum ferritin levels and reduces liver iron, which can help patients live longer.^7,8

How is it given? 

Oral administration of deferoxamine is ineffective. Similarly, intramuscular (IM) administration is inadequate. Therefore, DFO is not recommended for oral or intramuscular use; instead, continuous intravenous (Into the vein /IV) or subcutaneous (under the skin) infusion is advised.⁷

How does it work?

DFO works by binding to iron in the body at a 1:1 ratio, meaning one molecule of DFO binds to one molecule of iron. It helps release stored iron from old red blood cells, which is then excreted in urine and faeces.⁷

Compliance

DFO requires injection, which can be a barrier for many patients, leading some to avoid treatment.⁸

Side effects

Individuals treated with deferoxamine may face various side effects including:⁸ 

• Neurological problems 
• Gastrointestinal problems like stomach pain, diarrhoea, nausea, and vomiting 
• Skeletal changes 
• Delayed growth 
• Respiratory distress syndrome 
• Irritation at the site of injection
• Severe side effects like anaphylaxis may occur
• Low blood pressure (hypotension) 
• High pulmonary pressure (pulmonary hypertension) 
• A heightened risk of infections from bacteria that thrive on iron when it is released from the body’s stores during chelation therapy

Deferasirox (DFX)

Deferasirox is an oral iron chelator approved by the FDA in 2005. It is used for many iron overload conditions.⁸

How is it given? 

Two formulations of deferasirox have been introduced, both of them are oral formulations given once daily:⁸

• DFX dispersible tablet (DT) (Exjade®): The original formulation, which has a taste and gastrointestinal side effects
• DFX film-coated tablet (FCT) (Jadenu®): A newer formulation, which was introduced to overcome the side effects of the original formula

How does it work?

DFX works by binding to iron in the body at a 2:1 ratio, meaning two molecules of DFX bind to one molecule of iron.^7,8

Compliance

Treatment with DFX is very advantageous due to its once-daily dosing, but its high price makes it inaccessible to many people.⁸

The original DFX formula (DT) was associated with adherence challenges due to its side effects. These challenges were mitigated with the introduction of the new DFX formula (FCT), leading to better adherence.⁸

Side effects

The most frequent side effects of DFX include:^7,8 

• Stomach pain 
• Nausea 
• Vomiting 
• Diarrhoea 
• Skin rashes 
• Various complications 

Other more serious side effects are:

• Renal tubular dysfunction
• Metabolic acidosis
• Hypophosphatemia 
• Hypokalemia

Deferiprone (DFP)

Deferiprone is an oral iron chelator often used for patients who have not responded well to other chelation therapies like deferasirox or deferoxamine.⁷

How is it given? 

DFP has a short half-life, therefore it is given orally three times a day.⁸

How does it work?

DFP works by binding to iron in the body at a 3:1 ratio, meaning three molecules of DFP bind to one molecule of iron. It increases iron excretion through urine. It is thought to be particularly effective at removing excess iron from the heart.⁸

Compliance

DFP may improve adherence over other chelators. Although total iron excretion with DFP is slightly less than with Deferoxamine, DFP may have better cardioprotective effects because it can penetrate cells.⁸

Side effects

The side effects of DFP include: 

• Increased liver enzymes 
• Gastrointestinal problems 
• Joint pain 

The most severe adverse effects linked to DFP are agranulocytosis and neutropenia, both of which can be reversed upon discontinuation of therapy.⁷

Data suggest that patients treated with deferiprone experience lower rates of mortality and morbidity from cardiac events compared to those treated with deferoxamine.⁸

Summary

Ferroportin Disease (FD) is a genetic iron overload disorder caused by mutations in the SLC40A1 gene, leading to improper iron regulation in the body. It manifests in two forms: a mild form with elevated ferritin and low transferrin saturation, and a severe form resembling classic hemochromatosis with symptoms like joint pain and liver damage. 

Treatment options for this disease are phlebotomy and iron chelation. Iron chelation is vital in preventing organ damage, with key options including:

• Deferoxamine (DFO), an injectable with compliance challenges
• Deferasirox (DFX), an oral chelator with gastrointestinal and renal side effects
• Deferiprone (DFP), another oral option effective for cardiac protection but with risks of blood disorders