Low Ferritin And Inflammation

Overview

Ferritin is a protein that almost all organisms on the planet have, and is interlinked with iron by allowing its transport and storage while circulating in the blood. If levels of ferritin are low, this  can result in iron deficiency and/or iron-deficiency anaemia, which can lead to a myriad of symptoms. Low ferritin levels are also associated with some inflammatory diseases like rheumatoid arthritis. 

What is ferritin? 

Ferritin is an intracellular globular protein  that exists in the cytoplasm and within the mitochondria, and consists of 24 independent subunits. Together, these subunits unite/self-assemble  in heavy and light chains to produce what is referred to as a ‘nanocage’ that  holds the iron. Because of the cage-like structure, each ferritin molecule can store up to 4500 iron atoms inside its cavity, to play an important role in the iron metabolism within the cells.¹

This section will provide an overview of the genetics, structure, and function of ferritin. We will then move to discuss  low ferritin level , its causes and symptoms .

The blueprints of all proteins are genes. Genes provide instructions for the production of proteins in the form of nucleotide bases that  are then ‘translated’ and ‘transcribed’ into  amino acid sequences that assemble to form proteins. As ferritin is an integral protein and is found in nearly all living organisms, which means that its genes are highly conserved, i.e., there is little difference in the genes coding for ferritin between different species.  Ferritin is coded by three genes relating to its heavy chain and light chain, as well as a mitochondrial form. The heavy and light chain genes are homologous, being about 50% identical in different species. They share the same structure in vertebrates. The region that codes for the iron responsive element (IRE), which is a stem-loop structure, is highly conserved due to its importance. This importance is demonstrated by the occurrence of diseases such as iron overload due to mutations to this region. However, the mitochondrial version is distinct from the other two. Once these genes are read to make proteins that  form the structure of ferritin.¹

As previously mentioned, the structure of ferritin consists of 24 subunits. These subunits can be one of two types: a heavy chain and a light chain. The heavy chain is 183 amino acids in length and forms 6 helices and a beta sheet. On the other hand, the light chain is 175 amino in length and forms 7 helices. These subunit types amalgamate together to form a nanocage. The ratio of heavy  to light chains seems to be plastic with no set ratio. The differing ratio seems to relate to where the ferritin is in the body. For example, in the liver or spleen there is a higher ratio of light chains.² The nanocage formed can be used for several physiological functions.

Iron is present in the circulation in two forms, a free one that is considered toxic, being  a catalyst for the formation of free-radicals from reactive oxygen species via a Fenton reaction. 

The ‘non-toxic’ form of iron is that enclosed within the ferritin cage, owing to the ferroxidase activity mediated by the ferritin’s heavy chain units, which results in ‘hindering’ iron from being released, and being toxic. 

Free-radicals are essential for life, but they are highly reactive molecules that can cause damage to tissues.

Therefore, the body has a variety of processes to control the production of free radicals, ferritin being one of them. 

The iron molecule is present in two forms, the ferrous form, composed of two iron atoms, symbolised as Fe²⁺, and the ferric form that consists of three atoms, and is symbolised as Fe³⁺.

The ferroxidase reaction   implies the conversion of Fe²⁺ into Fe³⁺.

This conversion occurs at a specific point on the heavy chain known as the ‘diiron binding site’, or ‘the ferroxidase centre’. The Fe³⁺ is not as effective as acting as a catalyst for the Fenton reaction and so this process limits the production of destructive free-radicals. 

Once the three atoms of the ferric form (Fe⁺³) are made , the iron molecule  is displaced from the binding site by  a  ferrous (Fe²⁺)  molecule for the process to start over again. On the other hand, the light chain has no ferroxidase activity. The stored iron can then be used in a variety of physiological processes.

As will be discussed more later, ferritin seems to be involved in the immune response and inflammation. Overall, current knowledge states that ferritin rise is a biomarker for inflammation. In general, during an infection or chronic illness, ferritin genes are upregulated by inflammation and/or infection products, leading to the “leakage” of ferritin from damaged cells,³ which results in the rise of serum ferritin levels. 

Mitochondrial ferritin carries out a similar function to that of cytoplasmic ferritin, but is specific to the mitochondria, which means it  is involved in iron  metabolism and oxidative stress within the mitochondria,⁴ thus  allowing  it to protect  the mitochondria from oxidative stresses and regulate iron ion metabolism. 

Overall, ferritin’s main function is the transport and storage of iron in a non-toxic form, so it can be utilised  by cellular processes. Ferritin takes no active role in such processes, but the iron it releases can be used in a variety of functions. For example, macrophages sequester iron from damaged/old haemoglobin cells.

Low ferritin

Low ferritin  affects physiological functioning. As ferritin stores iron, lower ferritin levels mean a reduction of the maximum amount of iron to be stored, which in turn can result in  iron deficiency.

Overall, low ferritin levels mean less iron in the storage pool that may subsequently produce  iron deficiency. Iron deficiency must be distinguished from iron-deficiency anaemia. To avoid confusion, iron deficiency without anaemia will simply be referred to as  “iron depletion”, and if with anaemia, it will be referred to as “anaemic iron deficiency” or “iron-deficiency anaemia”. However, while iron depletion can persist with a normal blood cell count, it can also, in some cases, cause anaemia through  affecting the production of red blood cells in the bone marrow. 

Ferritin levels (low or high) can be verified by the  ferritin test, which  is a highly sensitive analysis  for assessing the ferritin levels in  the serum. 

Symptoms of low ferritin

As iron is an essential component in physiological functioning, there can be detrimental effects  of its deficiency. Low ferritin that causes deficiency is linked to several complications including: anaemia, fibromyalgia, hypothyroidism, inflammatory bowel syndrome, depression, ADHD, coeliac disease, and restless leg syndrome.^{5, 6, 7, 8, 9, 10}

These complications span several fields of medicine from haematology to neuroscience. To exhaustively list all the symptoms that these complications can produce, would be a very tedious task to cover  in this article. However, we will look at anaemia as an example as it is the most directly affected by iron deficiency.

Anaemic  iron deficiency can be a very serious condition. We need blood pumping around our body and delivering oxygen to perform physiological functions. Therefore, our lives can be hampered if we have lower amounts of blood. It can produce several symptoms including (See box 1).

Box 1: Symptoms and signs of anaemia

If you have anaemia, the doctor will perform an assessment of the total and detailed blood cell count and/or haemoglobin levels. This will indicate if there is a lesser blood cell count compromised blood indexes, including low haemoglobin level than  normal. Other tests may also be needed as, for example, ferritin and iron blood levels. Once iron-deficiency anaemia  is confirmed, you will start iron treatment in the form of  tablets, liquids, or in exceptionally severe cases, injections. 

It is worth mentioning that the  symptoms listed above can also present in cases of  iron depletion with no  anaemia . This can make the clinical diagnosis of iron depletion a challenge.^11,12 A doctor would naturally test for anaemia  but be returned with a full blood count.  Iron depletion can be suspected and tested for by assessing ferritin levels in blood, which  can, sometimes, be misleading, as iron levels can be low with normal ferritin levels, but, in this case, low  iron levels  can be shown with  iron staining of  aspirated bone marrow samples.

Causes of low ferritin

We have covered the complications that can arise from low ferritin levels but not the causes of low ferritin levels. As iron is primarily received through our diet, the first point where iron levels and ferritin levels can decrease, is at the point of intake, which can result from: 

• Plant-based diet with little iron
• Low caloric  intake with less iron that is required in a diet (especially important for pregnant women or growing children)

However, we can have a normal diet with the needed iron but still have decreased levels. The second point where iron and/or ferritin levels can decrease is absorption in the gut, which can be compromised in cases of

• Malabsorption e.g. diseases such as coeliac
• Achlorhydria - a condition in which  the stomach does not produce enough hydrochloric acid for digestion, and for absorption of iron from the gut

Once iron has been digested and absorbed, the levels can then be affected by excessive loss of iron from its body stores as with:

• Menorrhagia
• Gastrointestinal (GI) losses:
  • Peptic ulcer, erosion, oesophagitis
  • GI malignancy (more applicable to anaemic  iron deficiency)
  • Inflammatory bowel disease
  • Coeliac disease
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Parasites e.g. hookworms
• Pathological breakdown of red blood cells, acute or chronic, due to environmental or genetic factors
• Exfoliating skin conditions
• Haematuria
• Blood donation

Decreased ferritin and iron levels can also result from a functional standpoint in physiology:

• Bone marrow (where blood cells are formed ): in cases of inadequate supply of  iron despite adequate iron storage. 
• Chronic kidney and other inflammatory diseases like rheumatoid arthritis can affect iron levels. Interestingly, chronic inflammation can be a cause of low ferritin levels.
• Heart failure: possibly as a side effect of  medications used for the treatment of heart failure, e.g.  antiplatelets 

Therefore, low ferritin levels can be due to a variety of causes, at different levels. 

Is inflammation a cause of low ferritin levels?

As  listed above, chronic inflammatory conditions like rheumatoid arthritis can be  associated with low ferritin levels.³ The pattern of this association is difficult to predict or to figure out  as ferritin levels increase in the initial stages of inflammation. However, inflammation can be a cause of low ferritin levels as well. If the condition were to develop within an individual who already has a chronic inflammatory disease, it would significantly decrease their quality of life.

Low ferritin and inflammation 

Ferritin and inflammation are interlinked. High serum levels of ferritin  can act  as a biomarker of inflammation that helps to diagnose, follow up, prognosticate, and measure the effect of treatment of an inflammatory disease. In addition, elevated ferritin levels do not only occur in inflammatory disorders,  but in infections, acute or chronic, as well, as, for example  in COVID-19 infection.¹³ This makes ferritin  useful in diagnosing patients who are critically ill with COVID-19. 

Despite that,  there are cases where ferritin levels are low.

However, there is little literature that investigates the relationship of low ferritin levels and inflammation. Most studies focus on the increase, rather than the decrease, of  ferritin levels in inflammation, and its use as a biomarker. 

Measuring ferritin levels

Abnormal ferritin levels are assessed by the  ferritin test  that measures the levels of ferritin in the blood, and can indicate whether they are high or low. During the test, a sample of blood is taken from one of your big veins, using a needle, to be  then sent to a lab for analysis. 

The normal blood level of ferritin ranges in men between 11 and 307, and in women between 24 and 336 micrograms per litre . 

Low ferritin levels may  indicate that you have iron deficiency that can possibly develop into anaemia. This  may present with serious symptoms and signs, and should be treated immediately. 

However,  high ferritin levels can  indicate a variety of conditions. 

Treatment

With low ferritin levels associated with iron depletion or iron-deficiency anaemia, iron medications (tablets, liquids, or injections) ) will be prescribed to replenish your iron stores.

These medications can be taken for at least 6 months to keep iron  at healthy levels, and allow iron stores to replenish, and the process of red blood cell formation is fully restored.. However, there can be side effects from taking iron medications (box 2). However, despite these side effects, treatment should be thought through. 

Other medications may also be prescribed by the doctor to deal with other causes of low ferritin.

Box 2: Side effects of iron medications

• Constipation
• Stomach aches
• Heartburn
• Nausea 
• Dark stool
• Others

Summary

• Ferritin is a protein that is responsible for the transport and storage of iron while in the blood, and its release for use in physiological processes
• Some causes of decreased ferritin levels can lead to iron deficiency with or without iron-deficiency anaemia
• In some cases, inflammation may decrease ferritin levels, but in the majority of inflammatory conditions, ferritin levels increase, thus allowing it to act as an inflammatory biomarker
• Treatment of low ferritin depends on the cause, and if it is associated with iron-deficiency, it should include iron medications to replace wasted iron, and replenish its body stores to restore normal iron-dependent physiological functioning
• More medications may be added according to the underlying cause