What is aceruloplasminemia?

Aceruloplasminemia is an autosomal recessive neurodegenerative disorder, characterised by the absence of ceruloplasmin ferroxidase activity due to the ceruloplasmin gene containing a mutation.¹ Ceruloplasmin incorporates iron into the transferrin protein for transport.² Systemic and brain iron metabolism are both affected by aceruloplasminemia, causing iron to accumulate in tissues, particularly the brain, liver, pancreas and heart.³ 

Effective treatment is needed to manage symptoms and improve the quality of life of the patients. In this article, we are going to discuss comprehensive details of aceruloplasminemia, and how it is managed?

Pathophysiology

Ceruloplasmin, a copper-containing blood protein, requires its ferroxidase activity to oxidise and convert iron into a form that can be carried through the blood by a protein called transferrin.⁴ Without functional ceruloplasmin, in aceruloplasminemia, retention of iron and progressive overload occur in cells, leading to oxidative stress and tissue damage.

Moreover, cellular ion release is also reduced which causes iron deficiency anaemia as well as an inhibition on the production of red blood cells due to insufficient availability of iron (Iron-restricted erythropoiesis.² The iron overload causes patients to often exhibit neurological symptoms, diabetes, and liver disease.

Diagnostics

Interdisciplinary Diagnosis Approach

Aceruloplasminemia is the kind of disorder that demands an interdisciplinary approach toward its early diagnosis for the best prognosis by clinical evaluation, laboratory tests, and imaging studies.⁵

Clinical Evaluation and Family History

Diagnosis usually starts with the identification of symptoms and examination of family history in search of genetic patterns.

Biochemical Evaluation

Blood tests are followed by biochemical evaluation in order to analyse ceruloplasmin, copper, iron, and ferritin levels. Quite often, abnormal concentrations of these elements can be found in the patient.

Key Features: Mild anaemia, increased ferritin, and low saturation of transferrin.

Diagnosis in Aceruloplasminemia

With lack of actual good documentation, any suspicion of anaemia and/or increased ferritin, low transferrin will give a clue for the diagnosis of aceruloplasminemia.

Important Clinical Manifestations: Unexplained liver iron deposition, diabetes, and neurological disturbances such as behavioural changes in young adults.

MRI Studies

MRI is performed to confirm iron deposition, primarily in liver and brain tissues.

Whole-Brain MRI monitors iron deposition, while ex vivo techniques permit metal content studies in detailed cell types.

Genetic Testing

Genetic testing confirming the mutation of the ceruloplasmin gene allows one to clearly delineate the condition from others.

Differential Diagnosis: The similarity in presentation, as in Wilson's disease and others, will require genetic testing to ensure accuracy.

Aceruloplasminemia often requires treatment from multiple specialists and it must be diagnosed early for the best prognosis.⁵ Diagnosing aceruloplasminemia requires an interdisciplinary approach that includes clinical evaluation, laboratory tests and imaging studies. The initial method used for diagnosing aceruloplasminemia involves identifying typical symptoms and dissecting family history.⁶ This is followed by a biochemical evaluation which involves blood tests, analysing ceruloplasmin, copper, iron and ferritin levels. Aceruloplasminemia patients’ typically have abnormal blood concentrations of copper, iron and ferritin. Mild anaemia coupled with increased ferritin levels and low transferrin saturation have been identified as the three main signs of aceruloplasminemia when there is no obvious alternative diagnosis. Unexplained liver iron overload and diabetes mellitus can be clear indicators for aceruloplasminemia in young adults, as well as neurological dysfunctions such as behaviour changes and psychiatric disorders. Magnetic resonance imaging (MRI) studies are used to observe iron overload with accumulation in organs, specifically the liver and brain, aiding diagnosis. Not only is whole-brain MRI used to focus on iron accumulation, but ex vivo methods can be used to analyse the metal content of specific cell types.⁵ Genetic tests can also be carried out to identify ceruloplasmin gene mutations indicative of aceruloplasminemia. Other diseases such as Wilson’s disease can cause similar biochemical symptoms to aceruloplasminemia, so this is particularly useful for coming to an accurate diagnosis.

Treatment Options 

Current Treatment Options

Chelation Therapy

Iron chelators are generally used in the treatment of aceruloplasminemia because they decrease the iron overload present within tissues. Examples of iron chelators currently in use include the following: deferasirox, deferoxamine, and deferiprone.²

• Efficacy: In most patients, iron chelation therapy reduces systemic iron overload⁷
• Deferasirox: The US FDA approved deferasirox in 2005, which is taken once daily orally because of its half-life of ~12 hours^4,7
• Considerations:
  • Monitoring is important since there can be side effects such as renal changes
  • Deferasirox has been reported in some series not to change neurological manifestations
  • The use of chelation therapy before the neurological symptoms start might be more effective⁴
  • Some patients have been reported to stop the chelation therapy due to aggravated iron deficiency anaemia and participation in other treatments⁴

When treating aceruloplasminemia, iron chelators are usually used as they reduce the iron overload observed in tissues. Examples of iron chelators currently used include deferasirox, deferoxamine and deferiprone.² Iron chelation therapy is effective at reducing systemic iron overload for most patients. Deferasirox, which was approved for use in 2005 by the US Food and Drugs Administration (FDA), is taken orally once a day due to its half-life of approximately 12 hours.⁷ It is important to monitor the use of deferasirox for each patient as side effects, such as renal alterations can occur. Furthermore, deferasirox specifically has been found to not alter the neurological manifestations in some studies, which is reinforced by similar findings of iron chelation therapy in general.^4,7 Hence, different treatments could be more effective for managing the neurological symptoms associated with aceruloplasminemia. It has been suggested that using chelation therapy before neurological symptoms start is more effective. Nevertheless, alternative treatment options are important due to some individuals having to stop using chelation therapy because of iron deficiency anaemia being aggravated.⁴

Iron-Reducing agents

Phlebotomy:

Phlebotomy is the withdrawal of small volumes of blood from the patient to combat the accumulation of iron.⁷

Mechanism:

The body replaces losses of erythrocytes using iron, thereby reducing iron overload.

Problems:

The invasiveness and poor accessibility of veins make the procedure relatively less preferable.

Phlebotomy would exacerbate anaemia due to loss of erythrocytes.

Lifestyle Adjustments⁷

Dietary adjustments can be carried out to minimise iron accumulation:

• Avoid iron-containing food
• Emphasise food which impairs iron absorption, such as tea and coffee

A phlebotomy, which involves draining a small amount of blood from the patient, is often used to treat people suffering from iron overload.⁷ The patient will use iron to replace lost red blood cells, which reduces the iron overload experienced. However, because the procedure can be discomforting and accessing veins can be challenging, phlebotomy is not always favoured. In addition, phlebotomy can worsen anaemia due to the removal of red blood cells in the treatment. To reduce iron accumulation in aceruloplasminemia, simple lifestyle changes can be made such as changing diet. Avoiding iron-rich foods and focusing on foods that inhibit iron absorption, such as tea and coffee, is recommended.

Plasma Exchange and Fresh Frozen Plasma

Plasma Exchange Therapy

Plasma exchange involves the removal of the patient's plasma and replacing it with donor plasma that contains functional ceruloplasmin.

FFP:

• Plasma is drawn and frozen within hours to help preserve clotting factors and proteins
• Temporarily restores functional levels of ceruloplasmin
• Requires regular treatments as it is not a permanent solution

Plasma exchange therapy involves the removal of a patient’s plasma and replacing it with a donor’s plasma. The donor’s plasma would contain functional ceruloplasmin, helping to reduce symptoms associated with aceruloplasminemia. Specifically, fresh frozen plasma (FFP) can be used. FFP is plasma that has been collected from a donor and frozen within hours of collection to preserve its clotting factors and proteins. It is used to temporarily restore functional ceruloplasmin levels in patients. However, it is not permanent and requires regular treatments.

Emerging treatments 

Chelation and FFP combination

Overview:

Another application being tested for use in the treatment of aceruloplasminemia is a combination of iron chelation therapy and FFP therapy. This improves iron removal efficacy as well as ceruloplasmin replacement.

Evidence:

This combination treatment significantly reduced the brain iron deposition in two of the studies; thus, it relieves neurological symptoms.⁴

Significance:

This approach overcomes a key shortcoming of iron chelation therapy, which up until now has been less successful against neurological symptoms.

Combining iron chelation therapy with FFP therapy has been tested for its potential use in treating aceruloplasminemia. This should enhance the efficacy of iron removal and ceruloplasmin replacement. Two studies found that brain iron deposition was visibly reduced after using this combination therapy, showing that it can alleviate neurological symptoms in aceruloplasminemia.⁴ This is important because iron chelation therapy has been found to be less effective at combatting neurological symptoms associated with aceruloplasminemia.

Antioxidant therapy

Possible Alternatives

• Zinc Sulphate and Minocycline: Both display antioxidant property and can replace iron chelation therapy. Zinc sulphate acts by inhibiting the absorption of iron, while minocycline shows chelating properties⁴
• Vitamins E and C: These antioxidants are used in conjunction with other treatments to reduce tissue damage and manage systemic manifestations of aceruloplasminemia⁴

Zinc sulphate and minocycline have the potential to be used instead of iron chelation therapy due to their antioxidant function. Zinc sulphate also inhibits iron absorption and minocycline has chelating effects, making them both useful for aceruloplasminemia treatment. Vitamins E and C are antioxidants that have been used to reduce tissue damage when undergoing iron chelation therapy.⁴ These vitamins can be taken whilst undergoing other treatments and could help reduce symptoms and systemic manifestations of aceruloplasminemia.

Enzyme replacement therapy

Mechanism:

Plasma fractionation industrial processes purify therapeutic proteins. The plasma fractionation intermediate-derived ceruloplasmin has been a promising candidate for the treatment of aceruloplasminemia.⁸

Research Findings:

Plasma ceruloplasmin prevented haematological, hepatic, and neurological symptoms when administered to ceruloplasmin-deficient mice by direct injection.⁸

Implications:

This technique also pointed at the possibility of using certain proteins as a tool for replacement therapies and at a decrease in waste plasma.⁸

Enzyme replacement therapy has great potential for treating aceruloplasminemia. Proteins can be purified from individual intermediates in an industrial fractionation process to produce plasma-derived therapeutic proteins. Ceruloplasmin has been isolated from a plasma fractionation intermediate and shows potential for aceruloplasminemia treatment. When administered to ceruloplasmin-deficient mice via direct injection into the body cavity, this plasma-derived ceruloplasmin prevented haematological, hepatic and neurological symptoms.⁸ This highlights the potential of producing specific proteins for replacement therapy and reducing waste plasma, specifically for aceruloplasminemia. Gene Therapy

The Ultimate Goal:

Gene therapy would be used to correct the defect in the ceruloplasmin gene to avoid the functional deficiency of ceruloplasmin.

Benefits:

Theoretically, gene therapy could stop further disease processes and symptoms by addressing the cause.

Current Status:

Because of this, although still in development, gene therapy holds the most potential for being the most effective treatment for aceruloplasminemia once perfected.

The ultimate goal for the treatment of many rare diseases is gene therapy. This is no different for the treatment of aceruloplasminemia. Using gene therapy to correct the defective ceruloplasmin gene would be a very effective treatment, as it would prevent the lack of functional ceruloplasmin. Hence, it would hypothetically stop the development of the disease and the following symptoms that ensue. Whilst this has not yet been developed, if perfected, then it would likely be the most effective treatment.

FAQs

What causes aceruloplasminemia?

Aceruloplasminemia is caused by a genetic mutation in the ceruloplasmin gene. Ceruloplasmin, a copper-containing protein, converts iron into a form that can be carried in the blood by transferrin. Iron accumulates in tissues when there is no functional ceruloplasmin.

Can aceruloplasminemia be cured?

Currently, aceruloplasminemia has no cure. The focus of treatment is symptom management and prevention of complications from iron overload. Gene therapy research may result in a possible cure later.

When should I see a doctor?

See a healthcare provider if you have persistent neurological symptoms, unexplained fatigue, diabetes, or liver problems. It is crucial for patients with aceruloplasminemia to receive an early diagnosis and prompt treatment.

Summary

Aceruloplasminemia is a rare neurodegenerative condition resulting from mutations in the ceruloplasmin gene, which cause a lack of ceruloplasmin ferroxidase activity. This results in the build-up of iron in tissues such as the brain, heart, liver, and pancreas, causing oxidative stress and tissue damage. The diagnosis involves clinical evaluation, laboratory tests, and imaging studies to observe iron overload and other signs. Treatment options such as iron chelation, phlebotomy and plasma exchange aim to reduce iron overload and reduce symptoms. Emerging treatments such as combined chelation and FFP therapy could improve patient outcomes. To currently treat this condition, regular monitoring is necessary.