What Is Ferroportin Disease?

Introduction

Ferroportin disease, also known as haemochromatosis type 4, is a rare genetic disorder that affects the regulation of iron levels in the body. Iron plays a vital role in the transportation of oxygen around the body. Different from other types of haemochromatosis, ferroportin disease is caused by mutations in the SLC40A1 gene. This causes iron overload in the body as ferroportin - an important iron transport molecule doesn’t function properly or is unable to bind to its regulator, hepcidin. Iron build-up in the body is harmful, leading to complications in the organs such as the liver, heart, and pancreas. This article will give you an understanding of the role of iron transport in the body and the causes, symptoms, and treatments of ferroportin disease.

Iron metabolism and transport

Role of iron in the body

Iron is important in the body for oxygen transport, energy production, DNA synthesis, metabolism maintenance, immunity, and cell signalling.¹ Most of the iron in the body is stored in a molecule called haemoglobin, which is found in red blood cells. However, iron is also present in a type of white blood cell called macrophages and in liver cells.²

Mechanisms of iron absorption and transport

Iron in haemoglobin within red blood cells is recycled from old red blood cells to new red blood cells, ensuring that iron levels are high enough to transport oxygen throughout the body.² Additionally, iron can be absorbed from foods that are rich in iron, such as red meat or leafy greens. Iron from food is absorbed in the small intestine,   where it can be used for cellular processes when bound to a molecule called ferritin.² Macrophages obtain iron from old red blood cells.³

Iron from the intestine or macrophages can also be transported to other parts of the body by ferroportin.^2,3 As you might  expect, ferroportin disease is named after this molecule, as it is caused by a dysfunction of ferroportin.

Transferrin is a transporting molecule that allows iron to move through the bloodstream when bound to it.⁴

Another molecule called hepcidin is responsible for regulating ferroportin and is produced in the liver. When hepcidin binds to ferroportin, ferroportin is degraded, and iron isn’t released into the bloodstream. Therefore, if hepcidin levels are low, less ferroportin can be degraded, and more iron is moved into the blood.³

Genetics of ferroportin disease

Inheritance pattern and genetic factors

Ferroportin disease is an autosomal dominant condition, which means that inheriting a disease-causing mutation in a gene from just one parent is enough to inherit the condition. Ferroportin disease can be caused by several mutations in the solute carrier family 40 member 1 (SLC40A1) gene.⁵ The SLC40A1 gene codes for ferroportin and is normally responsible for iron transport from the intestine, macrophages, and the placenta into the blood.⁶

Impact of SLC40A1 gene mutations on ferroportin function

There are two subtypes of ferroportin disease, also called haemochromatosis type 4, which are:⁵

• Type 4A: caused by a lack-of-function mutation in the SLC40A1 gene
• Type 4B: caused by a gain-of-function mutation in the SLC40A1 gene

Haemochromatosis type 4A inhibits the normal function of ferroportin in exporting iron from the body. Ferroportin exports less iron, causing an excess of iron to accumulate in various organs and generally reduces iron levels in the blood.⁷

In Haemochromatosis type 4B ferroportin function isn’t stopped, instead, ferroportin becomes resistant to hepcidin binding, preventing ferroportin from being degraded. This leads to the continuous absorption of iron into organs.^4,7

Clinical presentation

Symptoms of ferroportin disease

Common symptoms include:^6,8

• Fatigue 
• Weakness
• Joint pain
• Abdominal pain
• Skin discolouration/hyperpigmentation
• Irregular heartbeat
• Erectile dysfunction 
• Low sex drive

Age of onset and disease severity variability

Ferroportin disease can occur at any age.⁵ There are four types of haemochromatosis, of which ferroportin disease is type 4. The age of onset in ferroportin disease differs from other types of haemochromatosis, which typically  occur between ages 20-30 in type 2, ages 30-40 in type 3, and ages 40-50 in type 1.⁵

Complications and health impact

Iron overload and its effects on organs and tissues

Iron overload causes tissue damage in multiple organs, including:⁶

• Liver
• Heart
• Pancreas
• Pituitary gland
• Adrenal glands
• Joints
• Skin

Liver

Iron build-up in the liver can lead to liver cirrhosis and an increased risk of developing liver cancer (hepatocellular carcinoma). Typically, iron overload in the liver is identified through  an MRI or a biopsy, where a small sample is taken for microscopic examination⁶

Heart

Iron overload in the heart is more common in haemochromatosis caused by mutations other than in HFE, which includes ferroportin disease. Iron usually accumulates in the heart’s ventricles,, staining the heart’s ability to pump blood. Over time, this damage causes an irregular heartbeat (arrhythmia), dilated cardiomyopathy, where the heart muscles stretch and eventually heart failure if not treated.^6,9

Pancreas

Accumulation of iron in the pancreas can lead to diabetes mellitus due to pancreatic damage and exocrine pancreatic insufficiency due to problems with enzyme production for digesting food.⁶

Pituitary gland

Excess iron in the pituitary gland can lower hormone production of thyroid-stimulating hormone (TSH), adrenocorticotropic hormone (ACTH), follicle-stimulating hormone (FSH), luteinising hormone (LH), estrogen, and testosterone. These hormones are vital for reproductive health and should be tested for in patients experiencing symptoms of hormonal imbalances that result in lower sex drive and erectile dysfunction. To monitor hormone levels, a brain MRI and hormone testing may be performed.⁶

Adrenal glands

The adrenal glands can also be affected by iron build-up, leading to adrenal insufficiency, as they may not produce enough cortisol. Testing for adrenal gland dysfunction should only be performed if the patient exhibits symptoms.⁸

Joints

Iron deposits in the synovial fluid in the joints can cause progressive joint pain.⁹

Skin

Iron deposits can affect the skin, resulting in hyperpigmentation when iron levels become elevated  

Diagnosing ferroportin disease

Blood tests and biomarkers for iron overload

Diagnosis usually involves blood tests to test for elevated levels of ferritin in the blood and transferrin saturation, which is the percentage of the blood that is bound to transferrin, indicating high iron levels in the blood.6 It’s important to note that Increased ferritin levels can also result from other environmental factors, including acute or chronic liver disease, infections, inflammatory conditions, and in response to alcohol.  Therefore, these results alone are not sufficient for diagnosing ferroportin disease.⁶

Blood tests for haemochromatosis:⁶

• Ferritin levels are considered elevated when they exceed  300ng/ml ( assigned male at birth (AMAB)) and 200ng/ml ( assigned female at birth (AFAB))
• Transferrin saturation levels above 45%, when presented with elevated ferritin levels in the blood, suggest a need for genetic testing to confirm haemochromatosis.

Ferroportin disease often presents with elevated levels of ferritin in the blood but normal or low levels of transferrin saturation, which can help  to differentiate it from other types of haemochromatosis.^4,6

Genetic testing for confirmation

Each of the 4 types of haemochromatosis is caused by mutations in different genes. The most common genetic mutation associated with haemochromatosis is in the homeostatic iron regulator (HFE) gene, primarily linked to haemochromatosis type 1, accounting for roughly 95% of haemochromatosis cases. Type 2 haemochromatosis is caused by the hepcidin (HAMP) or hemojuvelin (HJV) genes, while the transferrin receptor 2 (TFR2) gene leads to type 3 haemochromatosis.⁶

For genetic testing in ferroportin disease (type 4 haemochromatosis), it is crucial to rule out the presence of a mutation in the HFE, HAMP, HJV, and TFR2 genes. To diagnose ferroportin disease, it is necessary to test for mutations in the SLC40A1 gene. However, some people with disease-causing mutations in SLC40A1 may not develop ferroportin disease, as the mutations can lead to varying levels of symptom severity. Genetic testing for ferroportin disease is typically recommended if there is a family history of the condition or if symptoms of iron overload are present.⁶

Management and treatment

Therapeutic approaches for iron reduction

The treatment of ferroportin disease focuses on managing the symptoms and complications of iron overload resulting from the dysfunction of the ferroportin protein. While there is no cure for the underlying genetic mutation, various approaches can help alleviate the effects of iron accumulation in the body. The treatments are similar to those used for other types of haemochromatosis. It is also important to continuously monitor iron levels in patients to determine the necessary treatments.⁸

Phlebotomy

Phlebotomy involves the use of a needle to withdraw blood from a vein. It is the primary treatment to manage iron overload in ferroportin disease. Phlebotomy is typically performed  1-2 times a week until iron levels return to normal. After reaching normal levels,  phlebotomy may be performed less frequently  - around 3-4 times a year. Lifelong treatment is necessary because iron levels can rise again.⁹ Phlebotomy has been shown to reverse damage to the liver, except in cases of advanced cirrhosis, and can also benefit the heart and reduce skin hyperpigmentation.⁶ 

Iron chelation therapy

Iron chelation therapy involves the removal of iron using medications. This treatment is not usually necessary for individuals with ferroportin disease, as phlebotomy is an effective option in most cases. However, it may be considered for individuals with advanced heart disease and anaemia. Desferrioxamine and deferasirox are two types of iron chelators that can be administered intravenously or orally.⁸

Dietary modifications to manage iron levels

To avoid further increasing iron levels, individuals with ferroportin disease should avoid iron supplements. Vitamin C improves iron uptake. Reducing the intake of iron-rich foods is also recommended. Foods high in vitamin C should not be consumed in large quantities. Alcohol consumption can worsen iron absorption and should be reduced or eliminated in people with liver cirrhosis combined with ferroportin disease.⁸

Management at advanced stages of disease

Despite the iron-reducing treatments available, patients with advanced liver disease related to haemochromatosis can experience complications. In these cases, liver transplants are often the only remaining treatment option. For patients with progressive joint pain resulting from iron build-up, joint replacement surgery may be necessary.⁸

Summary

Ferroportin Disease, also known as Type 4 hereditary hemochromatosis, is a genetic disorder characterised by disrupted iron metabolism. Iron is vital for oxygen transport and energy in the body. Iron transport involves the molecules transferrin, ferroportin, and hepcidin. Genetic mutations in the SLC40A1 gene cause Ferroportin Disease. Symptoms include fatigue, joint pain, and irregular heartbeat. Iron overload causes complications in the liver, heart, pancreas, pituitary gland, adrenal glands, joints, and skin. Diagnosis of ferroportin disease involves blood tests for ferritin and transferrin saturation, along with genetic testing for mutations in SLC40A1. Effective treatment options include phlebotomy and iron chelation, paired with dietary changes. In severe cases, liver transplants may be necessary. For patients with symptoms of iron overload, early testing and monitoring of iron levels is important for the management of ferroportin disease.