Overview 

Aceruloplasminemia is a rare condition that causes a buildup of iron in cells across the body, with the main affected organs being the brain, the pancreas, and the eyes. The unique build-up of iron in the brain distinguishes aceruloplasminemia from other iron overload disorders.¹ Despite it being a genetic condition, the age of onset ranges from infancy to late adulthood and varies in the rate of progression and symptom presentation.²

This article delves into the effect of iron overload in aceruloplasminemia and highlights the complications that may be experienced by those with the genetic disorder. 

What is aceruloplasminemia

Many disorders have long and complicated names. Whilst this can seem daunting, this naming system is used to help people read the word and partially understand the basics of the disorder. At a glance, aceruloplasminemia means ‘little to no ceruloplasmin in the plasma/blood’. Here is a word breakdown of aceruloplasminemia:

Iron overload in aceruloplasminemia 

The role of iron

Iron is a highly important mineral used in many biological processes. Eating foods with a good source of iron, like meat, eggs and leafy greens is important, as we do not naturally produce iron.³ The two most common forms of iron that we absorb from our diet are ferrous iron (Fe²⁺) and ferric iron (Fe³⁺).

One of the most important functions of iron in the body is to help make a protein called haemoglobin. This is a molecule found in red blood cells that binds to oxygen to transport it around the body via the bloodstream.⁴ Without haemoglobin, our organs wouldn’t receive enough oxygen, leaving us feeling tired and weak.

When we eat iron-rich foods, the natural pH of our bodies causes it to be converted into the Fe³⁺ form. However, to be absorbed by the enterocyte cells lining the small intestine, it must be changed into Fe²⁺.⁵

What is ceruloplasmin? 

Once inside these enterocytes, Fe²⁺ can be converted back to Fe³⁺ for storage, or exported out of the other side of the cells into the bloodstream. To be transported around in the blood, the iron needs to be in the correct shape to attach to the transporting molecule, known as transferrin.⁶ This means converting Fe²⁺ back into Fe³⁺. 

In healthy individuals, one of the proteins that aids this process is called ceruloplasmin. It sits on the outside of the enterocyte to allow for the movement of iron from cells into the bloodstream.⁷ Ceruloplasmin is mainly made in the liver, but small amounts are also made by cells in the retina and pancreas, as well as immune cells, like macrophages in the body, and astrocytes in the brain.^{8, 9}

Ceruloplasmin has an additional protective effect.¹⁰ The Fe²⁺ form of iron can be quite toxic as it releases free radicals. These are highly reactive particles that want to steal electrons from DNA and other molecules, which in turn destabilise otherwise healthy cells.¹¹

Ceruloplasmin’s role in converting Fe²⁺ into the Fe³⁺ form not only helps its movement into the plasma and bloodstream but also acts as an antioxidant by pairing up with free radicals to stop them from causing damage.¹⁰

How the lack of ceruloplasmin leads to iron accumulation

Dysfunction or complete lack of ceruloplasmin in the body reduces the amount of iron that enters the bloodstream from the enterocytes. However, dietary iron is still absorbed into the enterocytes that line the small intestine. Since absorption remains at the same level, but the export is significantly reduced, iron begins to build up inside the enterocytes, leading to iron overload.²

Complications of aceruloplasminemia

Blood-related

Iron is one of the main components of red blood cells. As previously mentioned, its role in the production of haemoglobin is central to the ability of red blood cells to carry oxygen around the body.⁴ The lack of ceruloplasmin in those with aceruloplasminemia means iron in the Fe³⁺ form cannot be sent to the bone marrow for red blood cell production. The red blood cells that are made tend to be a lot smaller as they are missing the haemoglobin component.⁵ As a result, 80% of people with aceruloplasminemia have iron-restricted microcytic anaemia, a condition resulting in reduced oxygen delivery to the tissues of the body.² Symptoms of this type of anaemia are general weakness, dizziness and an increased heart rate. 

Neurological

One of the main complications seen in 68% of people with aceruloplasminemia is related to the buildup of iron in the brain, causing neurological issues.² For this reason, aceruloplasminemia is primarily described as a neurodegenerative disorder. Degeneration of brain tissue is largely irreversible, therefore recognising aceruloplasminemia in its early stages is vital to prevent further brain damage. 

The neurological complications seen in aceruloplasminemia will vary depending on where in the brain the iron accumulation occurs.¹² The table below highlights the regions of the brain that have been linked to iron buildup in aceruloplasminemia, and the associated symptoms. 

Pancreatic 

The presence of diabetes is also seen as an early indicator, with reports of 70% of individuals with aceruloplasminemia showing signs of diabetes.¹⁸

In healthy individuals, the cells in the pancreas respond to the intake of sugar by producing a hormone called insulin. Insulin plays a vital role in encouraging the uptake of sugar into cells, so it can be used for energy. In diabetes, the pancreatic cells become damaged and are unable to release insulin which results in increased blood sugar.²

It is the gradual build-up of iron in the pancreas that drives the dysfunction seen in aceruloplasminemia. As a result, the pancreatic cells are damaged by the free radicals and unable to release insulin.¹⁹

Visual

Another main complication seen in aceruloplasminemia is eye disease. Around 76% of people with this disorder experience retinal degeneration, which is progressive damage to the back of the eye.² This damage can be caused directly by an iron buildup in the retinal cells or as a result of diabetes induced by aceruloplasminemia.

The retina is located at the back of the eye and consists of a layer of cells that captures incoming light and converts it into signals that are processed in the brain, allowing us to see. The lack of ceruloplasmin in aceruloplasminemia means that Fe²⁺ can’t be converted into Fe³⁺, leaving free radicals free to damage the retinal cells, resulting in retinal degeneration.²⁰

Eye disease is also something to look out for in diabetes. A large network of tiny blood vessels supplies the eyes with oxygen and nutrients. As people with diabetes are unable to produce insulin, they often experience high blood sugar. Over time, high volumes of sugar in the blood can damage the eye and cause the gradual loss of vision.²¹

Summary 

There is a main triad of complications seen in individuals with aceruloplasminemia, those being neurological problems, retinal degradation and diabetes. Although these symptoms are the most common, iron overload in aceruloplasminemia has damaging effects across all systems of the body. For this reason, it is important to watch out for the onset of these symptoms, particularly if there is a family history of aceruloplasminemia.