Introduction

Overview of ferroportin disease

Ferroportin disease is a rare genetic disorder that occurs when abnormal iron accumulation occurs in the body. This disease, also called haemochromatosis type 4, is caused by genetic changes (mutations) in the SLC40A1 gene. This gene is responsible for the production of the ferroportin protein, which aids the transport of iron in and out of cells. Mutations in the SLC40A1 gene cause insufficient production of the ferroportin protein and result in the unusual accumulation of iron in the cells and tissues of the body. Thus, ferroportin disease is classified as an iron overload disorder.¹ 

Ferroportin disease is an autosomal dominant disorder, which means that both male and female children are equally susceptible (50% chance) to acquiring the disease from the parent in each pregnancy (NORD). Only one copy of the gene carrying the mutation is required for the disease to be passed on to your children (autosomal dominant genetic disorder). 

Haemochromatosis type 4 can be divided into two types:

• Type 4A
• Type 4B

Ferroportin disease is commonly seen in patients of southern European ancestry but can affect all races and ethnicities (NIH). 

Importance of iron regulation

Iron is an essential micronutrient, which plays a role in several cellular processes like enzyme activity, the transport of oxygen in red blood cells through haemoglobin (a protein compound containing iron) to all areas in the body, DNA synthesis, electron transport, and the production of hormones.² Inadequate intake of dietary iron in the body can cause iron deficiency anaemia, which is one of the most common nutritional deficiency disorders in the world (WHO).  An overload or excess of iron in the body can cause tissue damage and diseases like liver fibrosis, cardiomyopathy, endocrine dysfunction, and diabetes mellitus.³ Therefore, iron regulation and homeostasis (a state of balance)are extremely important for a healthy body. Iron homeostasis is achieved by regulating the amount of iron absorbed from your diet. 

Iron from our diet is absorbed by the intestines and macrophages (a type of white blood cell) are responsible for the iron recycling process in our body.⁴ Normal levels of iron in your plasma range from 12 to 25 μM/L.⁵ Iron is exported from enterocytes (cells in the intestine walls) and macrophages in their ferrous form (Fe²⁺) with the help of a transmembrane protein called ferroportin.³ Ferroportin releases the stored iron from these cells into the systemic circulation of the body to recycle and regulate iron levels. The expression of the ferroportin protein is regulated by hepcidin, a liver hormone responsible for iron regulation.⁵ Hepcidin can reduce iron export by binding to ferroportin and inducing its degradation. In short, high levels of plasma iron are due to low levels of hepcidin and vice versa.⁶ Iron is then oxidised to its ferric form (Fe³⁺) and then recycled in the bloodstream with the help of transferrin, which deposits this iron in the form of ferritin molecules stored in the liver, spleen, and bone marrow.² 

Pathophysiology of ferroportin disease

In ferroportin disease, mutations to the SLC40A1 gene disrupt the iron recycling process, which causes an overaccumulation of iron in the cells and tissues of the body.⁴ Mutations to ferroportin have been categorised into two types namely, mutants that are unable to reach the cell surface and mutants that do not respond to hepcidin.⁴ In the first type of mutation (type 4B), these ferroportin molecules are unable to reach the cell membrane from the endoplasmic reticulum, which disrupts the iron export from the cell. Here, iron absorption in the intestines remains unaffected but iron recycling from macrophages is interrupted, which causes low saturated transferrin levels in your blood plasma. This has been defined as the pathophysiology of ferroportin disease.¹ 

In the second type of mutation (type 4A), these ferroportin molecules are able to reach the cell membrane for iron export but do not respond to the hepcidin hormone, which controls and degrades ferroportin to regulate iron homeostasis. Here, iron absorption and export in enterocytes and macrophages would occur at a higher rate causing high saturated levels of transferrin to cope with the high levels of plasma iron. It leads to an overaccumulation of iron in the tissues and has been identified as the pathophysiology for a rare form of hereditary haemochromatosis called ferroportin-associated haemochromatosis.¹ 

Symptoms and diagnosis

Common symptoms of ferroportin disease include:

• Fatigue
• Abdominal pain
• Joint pain
• Heart abnormalities like arrhythmia (irregular heartbeat pattern)
• Lack of libido (sex drive)
• Mild liver damage (hepatic fibrosis)

Those diagnosed with type 4A haemochromatosis may not show symptoms of the disease. Those diagnosed with type 4B haemochromatosis might experience the same signs and symptoms as type 1 haemochromatosis. These symptoms can appear at any time in life. 

Mild liver damage can also progress to liver cirrhosis (scarring of the liver tissue) in some cases (NIH). 

Diagnosis of ferroportin disease includes the following biomarkers and tests:

• Serum ferritin
• Fasting serum iron
• Serum transferrin saturation
• Genetic testing
• In some cases, liver biopsy
• MRI

Some people show high serum levels of ferritin and low levels of saturated transferrin in their blood (NORD). 

Those with a family history of haemochromatosis, liver cirrhosis, or hepatocellular carcinoma are specific indications of ferroportin disease (MSD Manuals). 

Treatment for ferroportin disease

Once iron is absorbed into the body, there is no specific process related to the excretion of excess iron other than blood loss.² The most common treatment for cases of iron overload is through phlebotomy or venesection (removal of blood from the vein).¹ It must be noted that treatment for hereditary haemochromatosis cannot be followed in all cases of ferroportin disease. Phlebotomy might not work equally for all ferroportin disease patients so saturated transferrin levels and haemoglobin levels must be closely monitored during treatment. 

Generally, a balanced diet is recommended for all patients. Usually, hereditary haemochromatosis patients are advised to avoid food or supplements rich in vitamin C or iron. Vitamin C is said to increase the rate of iron absorption in the intestine (MSD Manuals). However, patients with ferroportin disease do not have any issue with iron absorption through the intestines based on the pathophysiology, so no such dietary restrictions are applicable.¹ Current studies are also investigating the therapeutic effect of antioxidants like vitamin E which protect cells from damage by unstable molecules called free radicals (NORD). 

Chelation therapy may be applicable in some cases.¹ This treatment involves medicine like deferasirox or desferrioxamine, which removes iron from the blood and is excreted through urine or faeces (NHS). 

Deferasirox is unlicensed for the treatment of haemochromatosis (it has not undergone extensive clinical trials for this use) so it is very important to enquire with your doctor that the benefits outweigh the risks. 

Genetic counselling is recommended for all affected patients and their families (NORD). 

Role of phlebotomy 

Phlebotomy is a simple invasive procedure, where you lie back in a chair and a needle is inserted into the vein in your arm that drains a small amount of blood (around 500 mL per session) (NHS). By removing blood, it signals the body to utilise its internal stores of iron to replace the lost iron, thereby reducing the levels of excess iron in the blood and preventing organ damage. This treatment occurs in two stages:

• Induction: frequent sessions take place to remove blood until normal levels of plasma iron are achieved
• Maintenance: less frequent sessions (two to four times a year) take place to regulate plasma iron levels

The induction stage lasts until serum ferritin levels reach 50-100 µg/L, after which maintenance is continued intermittently to maintain these levels (MSD Manuals).⁷ Due to limited research, there is no standard schedule for the treatment of ferroportin disease with phlebotomy but it has been suggested that patients should undergo monthly or bi-monthly sessions for one or two years depending on the mutation and maintenance therapy, which includes sessions every four to six months, should be continued for life.¹ 

Those with type 4A haemochromatosis are usually not treated with phlebotomy due to the increasing risk of complications like anaemia during the sessions (NORD). Those with type 4B haemochromatosis can be treated with phlebotomy because it resembles classic haemochromatosis (NORD). 

It is important to understand that phlebotomy is the only treatment for the symptoms of ferroportin disease and there is no cure to date. Hepcidin supplementation is suggested as an additional treatment option during the induction phase of phlebotomies and an alternative in the maintenance phase.⁷

Conclusion

Ferroportin disease, also called type 4 haemochromatosis, is a rare genetic disorder caused by mutations in the SLC40A1 gene. This gene is responsible for the production of ferroportin, a transmembrane protein which is pivotal in the export and recycling process of dietary iron in the body. Mutations to the gene cause a loss of function in ferroportin, which results in an overaccumulation of iron in the blood that gets deposited in the tissues and causes organ damage.

Common symptoms include fatigue, joint pain, abdominal pain, arrhythmia, lack of libido, and mild liver damage which may progress to liver cirrhosis. These symptoms are similar to type 1 haemochromatosis and only appear in patients diagnosed with type 4B, whereas type 4A patients may not show any symptoms.

Ferroportin disease can be diagnosed through biomarkers like serum ferritin, saturated transferrin, and fasting serum iron. Genetic testing is the most robust method of identifying the type of haemochromatosis. Ferroportin disease patients, specifically those diagnosed with type 4B, can be treated with phlebotomy. Phlebotomy is an invasive procedure, where a small amount of blood (usually 500 mL per session) is drawn through a needle inserted into a vein. These sessions must be continued intermittently for life after reaching the optimal serum ferritin levels (50-100 µg/L).

Other treatments include dietary restrictions like avoiding vitamin C or chelation therapy. Although there has been increasing insight into the pathophysiology of the disease, it is equally important to continue research towards optimising treatments and educating patients and their families on the disease through genetic counselling.