Overview

What is ferroportin disease?

Ferroportin disease is a rare hereditary disorder characterized by abnormal accumulation of iron in the body and it is caused by the variation and mutation of the gene SLC40A1. It is of two types, and symptoms of the disease vary from person to person. FD is also known as hemochromatosis type 4.¹

Ferroportin is a transmembrane protein responsible for the regulation and transport of iron.² Any variation or mutation in the SLC40A1 gene leads to low levels of ferroportin protein. As a consequence, excess amounts of iron accumulate in the body.³ It is present on almost every cell of the body that is needed for homeostasis of iron but mainly on enterocytes and macrophages of the liver, spleen and bone marrow. Moreover, it is also present in human mammary tissues, blood-brain barrier, synaptic vesicles and placenta.²

The prevalence of ferroportin disease is equal in men and women, irrespective of ethnicity and race. The treatment and management of disease are dependent on the type of disease and the severity of symptoms. The severe form of the disease should be treated immediately, otherwise it will lead to organ damage.⁴

Classification of ferroportin disease

Ferroportin disease is classified into two types

1. Classical or ferroportin disease type 4A
2. Non-classical or ferroportin disease type 4B⁵

Ferroportin (classical) Type 4A is a mild form of disease and it is represented by high levels of ferritin and low levels of transferrin in blood plasma. Ferroportin (non-classical) Type 4B is a severe form of ferroportin disease and it is represented by the increased level of transferrin saturation.⁵

Signs and symptoms

Clinical signs of ferroportin disease arise between the ages of 30 and 60, symptoms show more earlier in men than women, and usually show symptoms after menopause. In some cases, it is only detected through blood tests because no physical symptoms can be seen in patients.⁶

Primary symptoms

Each individual experiences different signs and symptoms, which can vary from patient to patient. Primary symptoms include:

• Weight loss
• Fatigue
• Anxiety, depression
• Joint pain
• Erectile dysfunction or decreased libido
• Irregular periods⁶

Secondary symptoms

As the disease progresses, the severity of the disease increases; it includes

• Hyperpigmentation
• Jaundice
• Swelling in the abdomen area, hands and feet
• Cardiac issues ( chest pain, shortness of breath, irregular heartbeat)
• Testicles become smaller in size
• Severe osteoporosis⁶

Aetiology 

Ferroportin disease is an autosomal genetic disorder and only a single copy of an abnormal gene could lead to ferroportin disease. The mutation of the SLC40A1 gene is the major reason for FD. This gene carries instructions to create ferroportin; it is a protein responsible for the transportation of the metabolism of iron and regulates the amount of iron in the body.⁴ Any variation or mutation in the SLC40A1 gene results in low levels of ferroportin protein which ultimately gives rise to abnormal accumulation of iron within cells, particularly macrophages and tissues.⁴ Moreover, hepcidin, a peptide hormone present in the liver, plays an important role in iron regulation. Any dysregulation in the making of hepcidin causes a disturbance in iron homeostasis.

Iron is an essential element present in cells, the body needs iron to grow, function, and provide energy. Low levels of iron cause anemia and high levels cause iron overload disorders. Therefore, it must remain in normal ranges.⁴

Diagnosis

In the past, liver biopsy was used as a diagnostic test, but as time proceeded, as understanding of genetic variation increased, the diagnosis was based on genetic testing.¹⁰

To diagnose ferroportin disease some important steps should consider; these are:

1. Firstly evaluate patient health by observing signs and symptoms. If individuals have darkened skin, weakness, joint pain, liver issues, increased glucose and serum ferritin; do perform lab tests to confirm the disease. Although, these symptoms are also associated with other illnesses. Therefore, a confirmation test is a must⁷
2. Furthermore, check transferrin levels because its level is increased in ferroportin disease i.e. greater than 80%, also check reactive protein with transferrin levels.
3. Perform a homozygous c282y mutation test to confirm the disease.
4. Assess serum ferritin levels to identify iron overload because it is closely related to each other⁷
5. MRI (magnetic resonance imaging) tests are also useful to diagnose ferroportin disease.¹⁰

Management and treatment of ferroportin disease:

Individuals with ferroportin disease have an iron overload in their bodies and since there is no natural mechanism of iron elimination from the body, therefore, it should be eliminated by synthetic ways. Two main methods are used for the removal of iron:

1. Phlebotomy (venesection)
2. Iron chelators⁸

Phlebotomy

Phlebotomy, also referred to as venesection, is the removal of blood from veins. It is the main treatment for the correction of iron overload. However, venesection cannot be well-tolerated by all patients, and anaemia will occur promptly with elevated serum ferritin.⁹

Advice: don't take vitamin C supplements or any food containing vitamin C because it may increase the absorption and release of iron from storage sites. Rarely will it cause cardiac issues.⁹

Iron chelators

Deferoxamine (iron chelator) is given as an iron chelator. It is an optional treatment for rare cases and patients who do not tolerate venesection or are contraindicated due to comorbidity with anaemia and patients having difficulty in blood withdrawal from the venous system.⁷

Management plan of phlebotomy

Initiation of therapy

Indication: Phlebotomy therapy is initiated at the stage ll level of ferroportin disease in relation to high levels of serum ferritin.⁷

Inhibition of therapy: phlebotomy therapy should be performed once a week for 1-2 years.9 The duration of therapy depends upon the variation of genes and the tolerance level of the patient. The removal of blood per session is 7 ml/kg, according to the patient's weight, and it should not exceed 550 ml per session.⁷

Purpose: The purpose of therapy is to achieve a level of serum ferritin less than 50μg/l.⁷

Follow-up plan: a test of serum ferritin is performed once a week and the result comes under normal ranges because the effectiveness of therapy relies on serum ferritin. When haemoglobin level is less than 11g/dl, immediately perform phlebotomy.⁷

Maintenance therapy

Phlebotomy therapy is continued every 1-4 months for the management of ferroportin disease, properly checking lab results of ferritin and haemoglobin.⁹ Ferritin level is checked after every 2 phlebotomy cycles and haemoglobin after 8 days. Maintaining normal levels of ferritin is the primary goal of therapy. Therapy is performed inside the hospital, under the supervision of a practitioner or at home by a nurse following proper standard guidelines.⁷

Outcomes of phlebotomy

The patient’s overall health symptoms will improve from treatment, but in some cases, it may worsen the conditions, for example joint pain becomes worse due to phlebotomy. Other comorbid conditions are reversed, and diabetes will not resolve even after the correction of iron overload.⁷

Future approaches to treat ferroportin disease

• Researchers explore other ways of treatment to treat illness and these are under development. Hepcidin mimetics are used as advanced treatment for ferroportin disease. These drugs can reduce iron accumulation in liver and heart¹¹
• In the coming years, gene therapies will also be considered a treatment option. Further, clinical data are needed to study its safety and efficacy
• Some drugs like ferroportin inhibitors are considered to be used in the future as a therapy¹¹

Summary 

Ferroportin disease (hemochromatosis type 4) is an autosomal hereditary disorder in which iron overload in the body. It can occur in any gender irrespective of ethnicity. Joint pain, infertility, decreased libido, hyperpigmentation, liver and spleen issues, cardiac issues, and diabetes are the clinical manifestations of FD. The main cause of the disease is mutation and variation in the SLC40A gene. As a result, low ferroportin levels arise, and ferroportin is responsible for iron regulation, metabolism and transportation. It is diagnosed through certain chemical tests such as serum ferritin, transferrin level, iron level, genetic testing and MRI can also be used. Two main therapies are used to cure FD; these are phlebotomy, the most common therapy and iron chelator. In recent years, more treatment plans are being considered which are now under study or research and more safety data are needed before use.