Introduction

Ferroportin disease is a rare genetic disorder affecting iron metabolism, specifically, it causes an abnormal iron overload in the body. The accumulation of iron in the body is toxic. Consequently, it can cause damage to the organs. The degree of damage is related to the amount of iron accumulated. Recognising the clinical presentations of ferroportin disease is crucial for quick diagnosis and effective treatment. Early identification is likely to prevent complications associated with iron overload before they can occur. As there are a variety of clinical presentations and symptoms, healthcare providers must be aware of them to differentiate them from other metabolic disorders caused by iron.¹

Overview of ferroportin disease

Ferroportin disease (FD) is caused by an autosomal dominant mutation. This means that only one copy of the gene needs to be inherited by the child from one parent. Therefore, people affected by the disorder have a 50% chance of passing the gene to their child. The risk of inheriting the disease is the same for both males and females. Research has found that the specific gene associated with FD is the SLC40A1 gene, with variants or mutations of this gene causing FD.

The SLC40A1 gene contains instructions for the creation of the protein ferroportin, involved in the metabolism (breakdown) of iron. Variants of this gene can lead to low levels of ferroportin, causing the accumulation of iron in the body. Other variants impact the export and metabolism of iron in varying degrees. 

Types of ferroportin disease

Classical FD is associated with loss-of-function (LOF) gene variants with characteristics, such as hyperferritinemia and iron overload in macrophages. Additionally, classical FD has a normal transferrin saturation. Transferrin is a protein that transports iron in the blood, therefore, transferrin saturation informs us of how much iron is bound to transferrin.^2,3 

Non-classical FD is associated with gain-of-function (GOF) gene variants, which are characterised by additional iron deposits in liver cells as it makes ferroportin resistant to hepcidin, a hormone that controls liver homeostasis. Non-classical FD has a high transferrin saturation. As non-classical FD causes additional iron deposits in liver cells, symptoms of this overload will include hepatomegaly and liver function abnormalities.^3,4 

Early clinical presentations

Symptoms of FD may begin at any stage of life, but they are more common in later stages. For women, symptoms typically begin after menopause. Initial symptoms appear as fatigue, weakness, anaemia (mild to moderate), low mood, weight loss and anxiety. Many people do not realise they have the disease due to the prevalence of the symptoms in day-to-day life, it may be a while before action is taken against the symptoms.¹ 

Hematologic symptoms

As FD affects iron metabolism, it manifests in blood issues. Moreover anaemia, other symptoms include microcytosis, smaller red blood cells than normal, and hypochromia, a reduced concentration of haemoglobin in the red blood cells.^1,2

Organ-specific manifestations

FD can affect entire organ systems, most commonly the liver, spleen, pancreas, heart and joints. 

• FD can cause scarring of the liver (cirrhosis), which ultimately can lead to a loss of liver function if untreated. Signs of cirrhosis may include tiredness, nausea, weight loss, yellowing of the skin, and itchy skin¹
• The spleen may be affected, resulting in splenomegaly, the enlarging of the spleen. Cirrhosis can be the cause of splenomegaly due to an increase in the size of blood vessels at the hands of liver disease⁵
• Iron overload damages the pancreas, causing resistance to insulin, and a subsequent build-up of glucose in the blood, which can lead to diabetes⁶
• Abnormalities of the heart rhythm (arrhythmias) are a common symptom of FD⁷ 
• Some people experience cardiomyopathy, a disease characterised by the difficulty of the heart to pump blood around the body. It is caused when iron builds up in a layer of the heart wall called the myocardium. This can be fatal, so it must be monitored closely⁸
• Iron overload can cause problems in the joints, including joint pain, inflammation, and stiff joints, all common symptoms of osteoarthritis⁹

Diagnostic criteria

A diagnosis of FD can be made by carrying out a combination of tests, including genetic testing, blood tests, imaging scans and in some cases, liver biopsies. Typically, multiple tests are needed to ensure a correct, timely diagnosis.

• Family history must be considered in great depth when making a diagnosis 
• Genetic testing aims to look at variations in the SLC40A1 gene, providing an indication of an individual’s likelihood of developing symptoms, and to which degree these symptoms will appear. Genetic testing completed after other diagnostic tools will confirm the diagnosis²
• Common blood tests used in the diagnosis include serum ferritin, transferrin saturation and a complete blood count. High ferritin blood levels and transferrin saturation indicate FD¹
• MRI testing of the abdominal region enables quantification of iron loading in the liver, spleen and spine¹

Differential diagnosis

Many diseases share symptoms with FD, making it difficult to distinguish between diseases. Comparisons must be made to make a differential diagnosis. The previously mentioned diagnostic tools are key to eliminating incorrect diagnoses. Diseases with similar symptoms include thalassemia, anaemia of chronic disease, and hereditary hemochromatosis.^1,2 

Management and treatment

Treatment of FD is typically targeted towards the symptoms displayed in each individual, therefore, treatment varies between individuals.^1,2

• Phlebotomy involves removing blood from an individual via their vein. Blood is removed to return blood iron levels to normal. It can be carried out periodically¹⁰
• Chelation therapy is used to remove iron from the body 
• Iron overload can be toxic to organs, therefore, it is essential that organs are monitored regularly to ensure this is not happening. If organs begin to be damaged, action must be implemented to prevent it from worsening^1,2
• Diet adjustments are often recommended so that individuals avoid eating iron-rich foods, unnecessarily increasing their iron levels. Iron supplements will also be avoided^1,2 

Prognosis and long-term outcomes

Like many diseases, the earlier detection and subsequent management, the better the long-term outcomes. Genetic counselling for affected families is sometimes suggested. This informs the family of the risk of the disease being inherited and enables earlier detection. Additionally, genetic counselling provides an opportunity for the family to be educated on the disease, teaching them to spot the symptoms when they start.

Summary

Ferroportin disease is a complex iron metabolism disorder characterised by iron overload in the blood. It manifests as a variety of clinical presentations, making a timely diagnosis difficult. A comprehensive diagnostic approach is required to differentiate this disease from others. Early diagnosis enables appropriate management strategies, including phlebotomy, chelation therapy, and lifestyle modification, which dramatically improve the prognosis and quality of life in the individual. In future, medical professionals must stay alert to the symptoms of this disease to ensure effective care. Additionally, more awareness is needed for the same reason.