Overview of aceruloplasminemia 

Aceruloplasminemia (ACP) is a rare inherited genetic progressive metabolic disorder that reduces the activity of the protein called ceruloplasmin (CP) due to mutations in the CP gene. CP is an enzyme that is needed to transport iron around the body. Iron fails to be transported when CP is mutated and accumulates in the body's organs.¹ Therefore, this reduces the regulation of iron around the body which further builds up over time if not treated.

One specific organ that iron accumulates in is the liver and this can cause many major issues which this article will talk about. The symptoms usually first appear between the ages of 20 to 60 and gradually worsen as the patient ages. We will also mention different diagnostic and treatment strategies that doctors can use to help remove the excess buildup of iron but also help treat the symptoms. 

Overview of healthy liver iron metabolism

As you may already know, the liver has many different functions, such as detoxification, gluconeogenesis, metabolism of nutrients such as carbohydrates, proteins and fats and much more. One key function of the liver is the regulation of iron homeostasis.² As you consume iron, some iron is transported to the liver to be stored as ferritin via the hepatic portal vein from the small intestine which is signalled by the hormone hepcidin.

When the rest of the body needs iron, ferritin is oxidised by the CP protein and this protein contains an enzyme called ferroxidase which contains copper. The copper helps carry out the chemical reaction which allows the oxidised ferritin to bind to another protein called transferrin to transport the iron around the body to where it is needed.^2,3

How does aceruloplasminemia affect the liver?

As mentioned before, ACP causes the liver to produce a mutated form of CP. This reduces the ability for ferritin to be oxidised and this prevents the iron from being able to be transported around the body via the bloodstream.¹ Over time, the ferritin builds up in the liver and symptoms arise later in life. This leads to iron-induced liver damage which is known as haemochromatosis.² This causes a domino effect and leads to a whole range of different symptoms including but not limited to: 

• Feeling tired all the time
• Weakness
• Weight Loss
• Irregular periods
• Darkening of the skin
• Feeling thirsty all the time
• Stiff painful joints
• Jaundice

When left untreated, the level of free iron increases which is much more reactive. This free iron can react with reactive oxygen species and increase the number of hydroxyl radicals causing cell and DNA damage. This can lead to fibrosis, which is scarring of the liver tissue.² This itself has no symptoms but if too much of the liver scars, it can lead to cirrhosis which can also cause an array of symptoms. Some of the symptoms were mentioned previously but it also includes: 

• Itchy skin
• Oedema 
• Vomiting blood

As the cells die, the Kupffer cells in the liver induce a proinflammatory response by releasing chemicals that cause inflammation. This can cause insulin resistance specific to the liver, which can lead to type II diabetes in the entire body.³ 

Another potential disease risk that can be caused by ACP is hepatocellular carcinoma. In other words, liver cancer. Of course, liver cancer can cause a domino effect of other symptoms and impair the entire function of the liver overall. The tumours usually grow and deprive normal liver cells of blood and the necessary nutrients they need to survive.² 

If these symptoms scare you, don't worry—scientists have developed several strategies to help diagnose and treat this disease.

Diagnostic approaches for ACP

ACP is a rare condition with some reports stating that it occurs in 1 in 2 million people.⁷ It is usually not one of the first things that doctors will think of when diagnosing the condition. However, due to the progressive nature of ACP, the earlier the diagnosis, the better the outcome. So, doctors may need to order an array of different tests such as:

• Blood tests of hepatic iron, serum ferritin levels and copper levels
• MRI scans
• Ultrasound
• Further laboratory tests
• Liver function tests
• Genetic tests

It is important to note that due to the disease having very few occurrences a lot of the research is based on case studies.⁴ This genetic condition will be very difficult to diagnose and can lead to many misdiagnoses such as being misdiagnosed as Wilson’s disease. 

Treatment strategies specific for liver disease caused by ACP

Due to the high levels of iron within organs, iron chelation therapy is often prescribed which are oral drugs that bind directly to the iron so that they are removed from the iron-deposited area by allowing it to dissolve in water and excreted through the kidneys. The drug Deferasiroxamine has been shown to significantly reduce iron accumulation in the liver and reduce serum ferritin.^2,4,5 Another effective method is using fresh-frozen human plasma. Supplementing with vitamin E and zinc reduces tissue damage.⁴

Avoiding iron supplements and excessive iron intake. Once haemochromatosis has become prevalent, the patient should also avoid vitamin C supplements. According to the NHS, haemochromatosis can also be treated via a venesection AKA phlebotomy where some of the patient's blood is removed weekly or 2-4 times a year based on your liver function.² Liver function will also have to be consistently monitored regularly to ensure the effectiveness of the treatment. Due to reduced liver function, it would also be best to reduce alcohol consumption as much as possible.

Genetic counselling

Because this is a genetic disease. Once a person in the family has been diagnosed with the disease, it is recommended for the family to undergo genetic counselling and receive the necessary information regarding the genetic disorders. For example, if a parent has been diagnosed with ACP, it is important to mention the risk of ACP being passed down to the children and suggest genetic screening for their children to prevent future symptoms if they have inherited the mutated gene. This way parents can make much more informed medical decisions.

Summary

To conclude, aceruloplasminemia is a rare autosomal recessive disease that results in a deficiency in ceruloplasmin which leads to the build-up of iron in organs such as the liver and this can lead to many different complications which can include, anaemia, weight loss and painful joints. It is important to seek treatment as early as possible when symptoms arise as the disease will be progressively worse over time.

After being diagnosed, patients will often undergo iron chelation or receive weekly venesections to reduce iron buildup. They will also have to avoid iron and vitamin C supplements as they will worsen the condition. It is also important to consider genetic counselling as it will help family members make well-informed medical conditions.