Overview

Ferroportin disease, which is also known as haemochromatosis type 4, is a rare genetic disorder.¹ It falls under the family of iron overload disorders. In ferroportin disease, there is an abnormal accumulation of iron within the body.¹ 

It is a genetic disorder, meaning that it is caused by changes in a particular gene, in this case, the SLC40A1 gene. Importantly, ferroportin disease and classic hereditary haemochromatosis are two separate disorders.^1,2 

This is because they are caused by variations in different genes. Each person experiences different symptoms, which can range from elevated levels of ferritin protein, or symptoms from other types of haemochromatosis.¹ 

This article will explore the genetics and inheritance patterns of ferroportin disease, including what it is, who gets it, and the treatment for the disease. 

Basics of ferroportin disease

Ferroportin is a protein in the body that acts as an iron transporter. This means that the protein is important for maintaining iron homeostasis in the body. It is involved in exporting iron from your cells into your bloodstream, which helps evenly distribute iron across your body.² 

In ferroportin disease, the iron overload in the body is usually found in organs such as the liver, which can eventually lead to liver disease, or the spleen, which can cause an enlarged spleen. It can also result in anaemia due to disrupted iron regulation.²

There are two forms of ferroportin disease, type 4A and type 4B.² 

The two types of ferroportin disease have different symptoms to each other. Type 4A ferroportin disease has mild symptoms such as hyperferritenaemia (excessive ferritin protein levels) and low saturated transferrin protein levels, which leads to ion overload in the liver and the spleen. 

This is generally because of impaired iron export, making iron unavailable for transport by the circulation transferrin proteins. This can cause mild anaemia and potentially lead to hepatic fibrosis (excessive tissue buildup in the liver).

Type 4B ferroportin disease is more severe than 4A.² The common symptoms include high plasma iron concentration, joint pain, diabetes, and cardiac arrhythmia. There is a higher level of iron deposits in the liver in type 4B, making liver damage more common. Liver iron deposition is greater in type 4B than in type 4A, and liver damage is more common. This leads to a higher chance of developing liver cirrhosis (scarring of the liver). 

Genetic basis of ferroportin disease

Ferroportin disease is caused by mutations in the SLC40A1 gene, which is located on chromosome 2.³ The SLC40A1 gene encodes for the ferroportin protein, which is an essential protein for regulating iron exportation from cells into the bloodstream. This is a vital process to help maintain the balance of iron within the body.^3,4 When the gene is mutated, this disrupts the function of the ferroportin protein. This disrupted function appears as impaired iron exportation and iron overload in the body. Many mutations can occur, but they generally all result in decreasing the ability of ferroportin to efficiently transport iron. This causes iron accumulation in the organs, which leads to the symptoms and possible organ failure.^3,4 

Inheritance patterns

Genetic diseases have different types of inheritance patterns.⁴ In the case of ferroportin disease, it follows an autosomal dominant inheritance pattern. This means that only one copy of a mutated SLC40A1 gene is needed to cause ferroportin disease. Therefore, if an affected person has a child with a non-affected person, the child has a 50% chance of inheriting the mutation and developing ferroportin disease. If both parents are affected, then the child has a 75% chance of inheriting the mutation and developing ferroportin disease. 

However, not everyone with the same mutation will have the same symptoms.^4,5 Ferroportin disease has a wide range of symptoms and severity levels, so someone can have little to no symptoms, or severe iron overload. If someone has the mutated gene but no symptoms, it is still possible for that individual to pass on the mutation to any children. 

Diagnosis and genetic testing

If someone is suspected of having ferroportin disease, there are three main steps that the general practitioner (GP) follows to confirm if the person has the disease.^5,6 The first step is initial blood tests, which will include four different tests (serum ferritin, transferrin saturation, full blood count, and liver function tests) to see if there is too much iron in the body.⁶ 

The serum ferritin indicates the amount of iron that is stored in the body. You are in the normal range if your level is between 25-300 ng/mL for adult males and 25-200 ng/mL for adult females.⁶ The transferrin saturation indicates how much iron is available to be used in the body. A normal level is when the saturation is up to 50% in people assigned male at birth (AMAB) and 40% in people assigned female at birth (AFAB).⁶ The full blood count is a test that indicates the concentration of red blood cells, white blood cells, and platelets within the blood.⁶ Finally, the liver function tests indicate the health of the liver by looking at the enzymes, proteins, and other components made by the liver.⁶ 

Step two is genetic testing, which occurs if the initial blood tests indicate results that are out of the normal range. The genetic test first checks for the more common form of genetic haemochromatosis, but if this test does not indicate that the individual has the necessary mutation, a further genetic test can be done to look for mutations of SLC40A1. 

The final stage is family genetic testing.⁶ Because ferroportin disease is an autosomal dominant disorder, it is highly likely that other members of the family will experience similar symptoms, including notable hyperferritinaemia. Both parents should be tested, as either parent can carry the mutation of ferroportin. Genetic testing can also help identify other family members who may be at risk of developing symptoms, even before iron levels noticeably increase. 

Once the diagnosis has been confirmed, more tests can be done to see how the high iron is affecting the body. These tests vary for each person depending on the level of iron overload. The most common organ affected is the spleen, which can be checked using imaging tests like magnetic resonance imaging (MRI). 

Treatment

Generally, treatment for ferroportin disease is based on the individual symptoms and severity.^5,6 If the individual has a mild form of ferroportin disease, they may not require any treatment, and treating these individuals with phlebotomy is complicated by the presence of anaemia. If the symptoms appear to be similar to those of classic haemochromatosis, the individual can be treated with phlebotomy. Sometimes, iron chelators may be used as a treatment to help bind the excess iron in the body. 

Summary

Ferroportin disease, also known as haemochromatosis type 4, is a rare genetic disorder. It can be divided into type A and type B. In ferroportin disease, there is an abnormal accumulation of iron within the body. It is a genetic disorder caused by mutations of the SLC40A1 gene. The SLC40A1 gene encodes for the ferroportin protein, which is an essential protein for regulating iron exportation from cells into the bloodstream. 

Ferroportin diseases follow an autosomal dominant inheritance pattern, where only one copy of the gene is needed for an individual to have the disease. Each person experiences different symptoms. 

Ferroportin disease is diagnosed through initial blood tests, genetic testing, and family genetic testing. Initial tests measure iron levels, transferrin saturation, full blood count, and liver function. 

Genetic testing checks for SLC40A1 mutations and family genetic testing identifies other family members at risk.