Iron and the body: Iron Deficiency, Haemachromatosis and Friedreich’s Ataxia

Iron is all around us.  But how is it used in our body?

Iron is all around us. But how is it used in our body?

One of the most common elements on earth, iron makes up a huge proportion of the earth’s crust and is used to make a multitude of useful things!  If I asked you to think of something made with iron, what would come to mind?  Steel…. Bridges… Nails… What about coordinating oxygen via haemoglobin in red blood cells?  Energy, through respiratory complexes in the mitochondria as iron-sulphur clusters?  Your immune system?  In fact, iron is found in a number of different proteins required throughout the body and is required for generation of neurotransmitters, hormones and other important molecules.  In this blog post we are going to show you what happens when regulation of iron goes wrong, and the diseases associated with this.

Iron deficiency

Iron deficiency anaemia is caused by a reduction in in haemoglobin or red cell concentration in blood. This may arise due to an increase in requirement for iron, such as during development or during treatment with erythropoiesis stimulating drugs to replace red blood cells during/after chronic kidney failure, chemotherapy, or certain HIV treatments. Poor diet or iron absorption due to infection or Crohn’s disease will also reduce the supply of iron. Increased loss of iron through blood donation, dialysis, surgery, trauma or bleeding might also result in a slight-moderate anaemic state. A long-term deficiency might be indicative of long-term blood loss, a presenting feature of diseases such as gastrointestinal malignancy. In 20% of cases however, no cause is found. Deficiency can often be treated by oral administration of iron supplements to keep iron stores topped up.

Of hospital anaemia cases not explained by blood loss, 50% are accountable to chronic infection and are rarely severe (however, there is a correlation between the severity of infection and the severity of infection). IL-6 is released by immune cells during infection and increases hepcidin expression, a hormone produced by the liver which binds the iron exporter ferroportin on macrophages and liver cells, causing its internalisation and degradation. This reduces the amount of iron exported from cells decreasing the amount available to the microbe, which can only get iron from its human host but requires the metal to become pathogenic.

Hypochromic microcytic anaemia

This is the most common clinical presentation of anaemia. Its diagnosis is by haemoglobin levels, transferrin saturation, and red blood cell volume, all of which consist of iron binding blood proteins. Patients suffer from fatigue, weakness, headaches and chest pain (due to compensatory mechanisms which deal with a low delivery of oxygen to tissues due to reduced haemoglobin levels). Cardiac activity is increased to try and pump the few oxygen carrying red blood cells around the body, causing palpitations, tachycardia and heart murmurs alongside increased breathing difficulty, all of which being indicative of the early stages of cardio-respiratory failure. Vasoconstriction limits blood flow to the skin so that it can be redistributed to the brain and heart, resulting in pallor skin. Long-term, the deficiency can be seen as flat/concave nails, sore tongue and dysphagia.  All in all, iron loss here results in a lack of oxygen delivery around the body, and the compensatory mechanisms used by the body to help get oxygen to these starved tissues results in more damage.

Haemochromatosis

The opposite of anaemia, this is a disorder of iron absorption and storage within the body. It is the most common inherited metabolism disorder in the Western world and has the characteristic pattern of tissue damage resulting from excess iron deposition. It primarily occurs in men between the ages of 40-60, and early symptoms such as lethargy, weakness, skin pallor, malaise and sleep disturbance are often subtle and easily overlooked. Increased iron uptake results in increased iron deposition in tissues such as the liver (causing cirrhosis and fibrosis), the endocrine system (resulting in diabetes) and cardiac tissue (resulting in myopathy and arrhythmia). Diagnosis is achieved by measuring serum ferritin concentration, taking an MRI of the liver and subsequent liver biopsy and gene typing.

Treatment of haemochromatosis may seem a little old fashioned, but regular phlebotomy (drawing of blood) often serves to decrease iron stores (this is a long way from the leeches of olden times). The drug Deferoxamine acts as an iron chelator, mopping up excess iron in the cell. If treated before cirrhosis or diabetes, the lifespan of a sufferer is normal.

Friedreich’s Ataxia

Friedreich’s ataxia is an autosomal recessive disease. It presents as gait disturbance (a lack of muscle coordination) and slurred speech. Ataxia (leading to muscle weakness) is caused by degeneration of neurones within the spinal cord resulting in atrophy of the posterior columns as well as progressive demyelination of nerve cells.  At a molecular level, it relates to the formation of iron-sulphur clusters within the mitochondria.

The gene encoding Frataxin (FXN) encodes a mitochondrial matrix targeted protein which contains a GAA trinucleotide repeat within its first intron. Expansion of this triplet-base does not influence the structure of the gene product, but does reduce its expression levels. In yeast, low expression levels of frataxin (homologue) results in slow growth, reduced respiration, sensitivity to oxidants, loss of mtDNA, mitochondrial iron accumulation, low cytosolic iron and high expression of iron uptake proteins.  In humans, frataxin has been shown to interact with scaffolding proteins (such as Isu1) required for iron-sulfur cluster formation, leading to the suggestion that Frataxin is an iron chaperone which delivers iron to the scaffolding complex, and that without it we cannot form this important structure required in a number of essential cellular processes.

So why does a lowering of iron-sulphur clusters result in disease? FXN patients also have damaging iron deposits in the heart and deficiencies in mitochondrial complexes I, II and III and aconitases- these are required as part of the Krebs cycle used to generate energy in the cell, and are all iron-sulphur cluster containing proteins.

 

Photo from: https://www.flickr.com/photos/22746515@N02/4800938997/

 

 

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