Low Ferritin And Inflammation

Overview

Ferritin is a protein that almost all organisms on the planet have.  It is interlinked with iron, thus allowing iron storage. Low blood levels of ferritin may point to impending iron deficiency, which can subsequently lead to a myriad of symptoms. However, low ferritin levels may also be associated with inflammatory diseases like rheumatoid arthritis. 

What is ferritin? 

Ferritin is an intracellular globular protein that consists of 24 subunits, which together form a nanocage which holds the iron. 

Image link here: 

https://commons.wikimedia.org/w/index.php?search=ferritin&title=Special:MediaSearch&go=Go&type=image

Image caption: the 3D structure of a ferritin nanocage.

This section will provide an overview of the genetics, structure, and function of ferritin. We will then move to discuss low ferritin (sometimes known as iron-deficiency anemia), its symptoms and its causes.

The blueprints of all proteins are genes, part of a cell’s DNA. Genes provide instructions for the production of proteins in the form of nucleotide bases which are then translated and transcribed into amino acid sequences that form proteins such as ferritin. As ferritin is found in nearly all living organisms, it is highly conserved. This means that there is little difference in the ferritin-coding gene among different species. Ferritin actually derives from 3 different genes, each encoding either its heavy chain, its light chain or its mitochondrial form. The heavy and light chain genes are almost 50% identical.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. These subunit types amalgamate together to form a nanocage. The ratio of heavy chains to light chains seems to be highly variable, depending on 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.

The main function of the ferritin molecule in the blood is iron storage. The nanocage can store 4500 iron atoms rendering them non-toxic.¹ When iron is present in a free form, it becomes toxic as it acts as a catalyst for the formation of reactive oxygen species or free-radicals, which, despite being essential for life, are highly reactive molecules, that can damage tissues. Therefore, the body has a variety of processes to control the production of free radicals, among which is ferritin, being able to store iron in a non-toxic form. 

Ferritin seems to be involved in the immune response and inflammation. During infection or chronic illness, high blood ferritin levels, due to “leakage” from damaged cells, under the effect of inflammatory products that can cause ferritin genes to become more active. 

Low ferritin

Low ferritin levels reduce the maximum amount of iron that can be stored, resulting in iron deficiency in the body.

An important distinction in iron deficiency is whether it is with or without anemia. To avoid confusion, iron deficiency without anemia will be referred to as “iron depletion”, but if anemia is attributed to iron deficiency, it will be referred to as “anemic iron deficiency”. However, while iron depletion can persist with a normal blood cell count, it can also in some cases cause anemic conditions due to affecting the production of blood cells. 

Consequences of low blood ferritin levels

Iron is an essential component of normal physiological function, there can be detrimental effects of iron deficiency. Low ferritin, causing iron deficiency is linked to several complications including anemia, fibromyalgia, hypothyroidism, inflammatory bowel syndrome, depression, ADHD, coeliac disease and restless leg syndrome.^{6, 7, 8, 9, 10, 11}

These complications span several fields of medicine from hematology to neuroscience. To list all the symptoms that these complications can produce would be a very long list which we will not cover in this article. However, we will look at anemia 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 (which uses iron to carry oxygen) pumping around our body and delivering oxygen to perform physiological functions. Therefore, our lives can be hampered if we have lower blood iron levels. It can produce several symptoms including:

• Fatigue/lack of energy/tiredness
• Shortness of breath
• Noticeable heartbeats (heart palpitations)
• Pale skin
• Hair loss and irregular nail growth
• Delayed skin wound healing
• Sore tongue
• Tinnitus
• Headaches

If you have anaemia, a doctor will perform a total blood cell count. This will show if there is a lesser amount of blood count than is normal. Once this is confirmed, you will start treatment such as iron tablets (see below).

The symptoms that are listed above can also manifest in iron depletion without anemia. This can make a diagnosis of iron depletion a difficult clinical challenge.^12,13 A doctor would naturally test for anemia but be returned with a full blood count in this case. After this, iron depletion can be suspected and tested for by ferritin levels. However, again ferritin levels can be misleading as iron levels can be low, despite normal ferritin levels.  The stages of iron deficiency are well described here.

Causes of low ferritin

As the body’s iron originates primarily in our diet, the first point where iron and ferritin levels can decrease is at the point of intake due to:

• Eating a plant-based diet with little iron
• Eating a low-caloric intake diet with less iron (especially in  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 or ferritin levels can decrease is absorption in the gut, where ferritin/iron levels can be affected:

• Iron malabsorption, e.g. in diseases such as coeliac disease
• Achlorhydria - a condition where the stomach does not produce enough hydrochloric acid for digestion

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

• Menorrhagia
• Gastrointestinal (GI) losses:
  • Peptic ulcer, erosion, oesophagitis
  • GI malignancy (more applicable to anemic iron deficiency)
  • Inflammatory bowel disease
  • Coeliac disease
  • Non-steroidal anti-inflammatory drugs (NSAIDs)
  • Parasites, e.g. hookworms
• Exfoliating skin conditions
• Haematuria
• Frequent blood donation

Decreased ferritin and iron levels can also result from:

• Bone marrow (where blood is produced) not receiving adequate amounts of iron despite adequate iron storage in its cells
• Chronic kidney disease and other chronic inflammatory diseases like rheumatoid arthritis 
• Medications for treating heart failure (e.g., anti-platelets)

Is inflammation a cause of low ferritin levels?

As was listed above, chronic inflammatory diseases, like rheumatoid arthritis, are associated with low ferritin levels. This association is counter-intuitive, as ferritin levels usually increase in the initial stages of inflammation. However, it has been shown that inflammation can also be a cause of low ferritin levels. ^3,4 

Low ferritin and inflammation 

Ferritin and inflammation are interlinked. High serum ferritin is a known marker of inflammation because inflammation causes ferritin to leak from the cells into the blood. This helps clinicians to diagnose chronic inflammatory diseases. 

Elevated ferritin levels not only occur in chronic inflammation but in acute inflammatory conditions, such as acute infection, as well,  which was found in COVID-19 infection.¹⁴ This made it useful in diagnosing COVID-19 patients who were critically ill. 

The reason that chronic inflammation is also associated with low ferritin levels is not yet certain, however.

Measuring ferritin levels

A diagnosis that relates to ferritin will use a ferritin test. This test 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 using a needle which is then sent to a lab for analysis. 

Normal blood levels of ferritin range between 24 and 336 micrograms per liter in men, and between 11 and 307 micrograms per liter in women.

Low ferritin levels can indicate that you have an iron deficiency which could possibly develop into anemia, which can present with serious symptoms and should be treated immediately. Conversely, high ferritin levels can indicate a variety of conditions, such as acute inflammation (see above). 

Treatment

With low ferritin levels, iron tablets (or drops in newborns and infants and liquid in children) will be prescribed to replace the iron that was lost from the body.  These can be taken for at least 6 months to keep iron levels at healthy levels and allow blood to replenish. However, there can be side effects from taking iron medications. These include constipation, stomach aches, heartburn, nausea and dark stools. Despite these side effects, treatment should be thought through.

Summary

• Ferritin is an iron-storing protein that then releases it for use in physiological processes
• Some causes of decreased ferritin levels can lead to iron deficiency with or without iron-deficiency anemia
• In some cases, inflammation may decrease ferritin levels, but in the majority of inflammatory conditions, ferritin levels increase, thus allowing its use 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