The storage form of iron, aka, ferritin, has been having quite a moment
There has been a lot of discussion recently around ferritin, what constitutes iron deficiency and whether the ranges we have been using have meant that people, particularly women have been walking around iron deficient while being told their blood results are ‘normal’.
We are going to get to all of that in this series. But before we start focusing on what your ferritin should be, we need to understand something fundamental. At the New School, fundamentals are vital; otherwise, students pick up bad habits and get all confused.
What actually happens to iron once you eat it? Eating iron is one thing but getting it from your plate, through your gut, into your bloodstream and ultimately into the cells is another. Unlike many other nutrients, iron is VERY tightly controlled. There is a reason for this tight control, and that is because too much free iron can lead to cellular toxicity (Papanikolaou, G., & Pantopoulos, K. (2005)
Before we dive into ferritin ranges, transferrin saturation, TIBC and all those lovely acronyms that make blood tests look like someone has accidentally given you a Scrabble board…let’s follow the iron.
If you like bullet point summaries, then here is the skinny on this blog:
- Iron does considerably more than prevent anaemia.
- It is needed to make haemoglobin and transport oxygen around the body.
- It is involved in mitochondrial energy production.
- Thyroid peroxidase (TPO), an enzyme required for thyroid hormone synthesis, is iron-dependent.
- Iron sits at the centre of the haem group in cytochrome P450 enzymes involved in oxidative metabolismMetabolism is not a calorie-burning furnace that sits somewhere near your belly button, deciding whether you can fit into last year's jeans. Metabolism is the set of chemical processes taking place inside your body every second of every day, keeping you alive. including detox.
- Most of the body’s iron is recycled, rather than continually replaced from food.
- Dietary iron is predominantly absorbed in the small intestine, but getting it there and absorbing it requires several steps.
- Iron does not automatically enter your bloodstream from the gut
- Ferroportin (the ‘iron gates’)is the proteinProtein is one of the three main macronutrients, alongside fats and carbohydrates, yet for many years it was often the forgotten member of the trio. More recently, protein has become something of a celebrity in the nutrition world, appearing in everything from snack bars and cereals to coffee and desserts. Whilst the marketing can sometimes get a little carried away, the truth is that protein is essential for human health. Every cell in the body relies on it. Protein helps build and repair tissues, supports immune function, forms enzymes and hormones, transports nutrients, and helps maintain muscle mass, particularly as we age. that allows iron to leave certain cells and enter the circulation.
- Hepcidin, made predominantly by the liver, regulates ferroportin (iron gates) and therefore has enormous influence over how much iron becomes available.
- When iron is needed, hepcidin can fall and more iron can be released into circulation.
- Simply saying “eat more iron” or continually adding iron supplements may miss the reason iron is low in the first place.
- And ferritin? We’ll come to our iron larder shortly. But ferritin alone doesn’t tell the whole iron story.
If you like the full-fat version… keep reading.
Why do we need iron anyway?
Mention iron and most people immediately think of blood. And yes, that’s a pretty important job. Iron forms part of haem, which sits within haemoglobin inside our red blood cells. Haemoglobin binds oxygen in the lungs and helps transport it around the body. Which means when iron availability becomes inadequate, one of the places you may eventually notice it is in your ability to get oxygen where it needs to go.
Suddenly the stairs you’ve climbed every day for the last ten years can feel suspiciously like the Himalayas. You reach the top thinking, ‘Why am I breathing like I’ve just run for a bus?’
Your muscles may feel heavy. Exercise feels harder. Your heart may race or pound. You may feel dizzy or light-headed.
But iron’s resume is much longer than ‘helps make haemoglobin’. Seriously!
Iron and your mitochondria: Your mitochondria, the little energy-producing structures inside your cells, also rely on iron-containing proteins. Iron is involved in the electron transport chain, where energy from food is ultimately used to generate ATP (your currency of energy).
So when iron availability is inadequate, it isn’t difficult to understand why fatigue can become such a prominent symptom. It is not merely about having enough oxygen arriving at the cell. The cell also has to be able to use the fuel once it arrives.
Iron and your thyroid: This one is particularly important to us at the New School, as we see this too often, in our clinics.
Thyroid peroxidase (TPO) is a haem-containing enzyme (haem has iron at its core). TPO helps catalyse key reactions involved in producing thyroid hormones, including oxidising iodide and iodinating tyrosine residues on thyroglobulin. There is lots more on thyroid in our Thyroid 101 course HERE.
Iron deficiency has been shown to impair thyroid hormone synthesis by reducing the activity of haem-dependent thyroid peroxidase. This is one reason we don’t teach thyroid health as simply: High TSH means a thyroid problem and end of story.
The thyroid needs nutrients. It needs a functioning gut. It needs amino acids. It needs minerals. It needs the right biochemical environment. But we digress; want more on this? Check out the Thyroid 101 course.
And then there are the CYP450 enzymes…Iron also sits at the heart of the haem group within cytochrome P450 enzymes. If you have heard us teaching about Phase I metabolism in the liver, these will sound familiar. Cytochrome P450 enzymes are involved in the oxidative metabolism of an enormous range of compounds, including medications, steroid hormones and substances from our environment, which include plenty of toxins.
So, iron isn’t just about whether you are anaemic. It is key in so many biochemical reactions in your body.
Low iron symptoms
Sometimes, low iron symptoms can be serious; other times, they’re mild. You might simply notice that you are no longer functioning quite like yourself.
Possible symptoms associated with iron deficiency can include:
- fatigue and reduced stamina
- breathlessness, particularly on exertion
- palpitations
- dizziness or light-headedness
- headaches
- feeling cold
- cold hands and feet
- difficulty concentrating
- restless legs
- hair shedding
- brittle nails
- pallor
Sometimes eyebrows and hair seem to have entered their own moulting season. Of course, none of these symptoms belong exclusively to iron deficiency. Fatigue does not automatically mean low iron. Hair loss does not automatically mean low ferritin. Cold hands do not automatically mean you need an iron supplement. Symptoms give us clues, they don’t give us a diagnosis.
Let’s follow your iron from the dinner plate.
Imagine you’ve just eaten a meal containing iron. Perhaps that’s beef. Perhaps lentils, chickpeas, tofu, pumpkin seeds, leafy greens or another iron-containing food.
BTW, despite what the internet sometimes suggests, iron is not exclusively found in steak. Dietary iron comes broadly in two forms: haem iron, predominantly from animal foods, and non-haem iron, found in plant foods as well as some animal foods.
Their absorption pathways differ, but for our journey we will focus on non-haem iron because it beautifully demonstrates how regulated this process is.
Imagine you have just eaten a meal containing iron. Perhaps that’s beef. Perhaps lentils, chickpeas, tofu, pumpkin seeds, leafy greens or another iron-containing food. And despite what the internet sometimes suggests, iron does not exclusively live inside steak.
Dietary iron comes broadly in two forms: haem iron, predominantly from animal foods, and non-haem iron, found in plant foods as well as some animal foods.
Their absorption pathways differ, but for our journey we will focus on non-haem iron because it beautifully demonstrates how regulated this process is.
Stop 1: The stomach
Food arrives in the stomach. And your stomach isn’t simply a holding bag while dinner waits for permission to continue south. Its acidic environment helps release nutrients from the food matrix and supports the digestive processes necessary for their subsequent absorption.
This includes iron. Already we have our first clue as to why: “But I eat loads of iron!” doesn’t necessarily mean your iron larder (ferritin) is going to be ‘well stocked’.
- What is happening to that food once you’ve swallowed it?
- What is your gastric environment like?
- Are you taking acid-suppressing medication?
- How well are you digesting?
Iron still has quite a journey ahead of it.
Stop 2: Welcome to the duodenum
Your partially digested food leaves the stomach and enters the first part of the small intestine, the duodenum. This is prime real estate for iron absorption. Much dietary non-haem iron arrives in the ferric Fe³⁺ form. Stay with us; we won’t get too biochemical on you.
But the intestinal transporter that takes non-haem iron into the enterocyte predominantly transports the ferrous Fe²⁺ form. So, can you see the 3+ needs to be reduced to the 2+?
An enzyme on the intestinal brush border called duodenal cytochrome b (also called ferrireductase) helps reduce Fe³⁺ to Fe²⁺. And this enzyme requires. This enzyme uses electrons supplied by ascorbate (vitamin C) to help reduce Fe³⁺ to Fe²⁺. You see why vitamin C is key in the absorption of iron? Now it is ready for its next stage. Already considerably more complicated than, eat spinach and iron goes into the blood.
Stop 3: Iron enters the intestinal cell
Fe²⁺ can now be transported into the enterocyte (one of the cells lining the intestine). One of the key transporters involved is, DMT1, Divalent Metal Transporter 1 (this is a protein, it is a bit like a bus). It has to take the non-haem iron from the intestines into the intestinal cell, an enterocyte. Iron has entered the enterocyte but it still has to enter your bloodstream.
This step is crucial because your body has to decide what to do with it.
Stop 4: The iron gate
On the other side of that enterocyte sits another protein, ferroportin. Ferroportin is currently recognised as the body’s only known cellular iron exporter. It allows iron to leave cells such as enterocytes and macrophages and move into the circulation. Think of ferroportin as an iron gate.
Gate open? Iron can leave the cell and enter the blood. Gate shut? Iron stays put. So who has enormous influence over that gate? Meet one of the most important characters in our story, hepcidin. We call it the iron gatekeeper.
Hepcidin is a small peptide hormone produced predominantly by the liver. When hepcidin rises, it binds to ferroportin, leading to its internalisation and degradation (Ganz, T. (2003).
In practical terms, the iron gate closes. Therefore, less iron leaves the enterocyte and enters the bloodstream. Hepcidin also influences the release of recycled iron from macrophages (immune cells), which will become very important shortly.
When the body needs more iron, hepcidin can fall and ferroportin remains available. The gate opens. More iron can move into circulation. Iron absorption is not simply determined by how much iron is sitting on your plate. Your body has a very big say in how much actually gets into your body.
Imagine two scenarios
A woman has her period. What happens next? This is where you may simply be in greater awe and wonder at the wisdom of your body. Women lose iron through menstrual blood.
The body isn’t supposed to simply shrug and say, ‘Well, you are a woman. What did you expect?’ After blood loss, falling iron availability and increased demand for red blood cell production signal the body to suppress hepcidin. Lower hepcidin levels mean ferroportin remains active, making more iron available for absorption and recycling.
So rather than thinking: period = lose iron = inevitably become iron deficient. Instead ask, “Is the body able to replace what has been lost?”
Of course, the amount of blood loss matters enormously. Heavy menstrual bleeding can exceed the body’s ability to compensate and is an important cause of iron deficiency. But there is another layer to this, because hepcidin responds to more than iron status.
Imagine you develop an infection, say the flu; your body suddenly has some serious work to do because not only do you like iron, but so does the organism (aka the virus). Many microorganisms require iron. So, during an infection and inflammation, the immune system can effectively reduce iron availability, otherwise the microorganisms will thrive.
Inflammatory signaling can increase hepatic hepcidin production, and as hepcidin rises, ferroportin falls, and the gate closes. Less iron is absorbed from the gut and less recycled iron is released into the circulation. From the body’s perspective, this can be protective, as it is attempting to withhold an important resource from invading microorganisms.
So, if you are acutely unwell and your iron markers change, the immediate conclusion should not necessarily be, ‘quick, more iron’. The body may be deliberately altering the distribution of iron.
Sometimes low circulating iron isn’t simply a food problem.
It can be a regulation problem (Moretti, D., et al. (2015). Once iron has successfully passed through the intestinal cell and into circulation, we don’t want reactive iron wandering freely. So it travels mainly bound to a transport protein called transferrin. Think of transferrin as the body’s iron transport system. It carries iron through the bloodstream and delivers it to tissues that require it, particularly the bone marrow, where enormous amounts of iron are needed to manufacture new red blood cells.
Cells have transferrin receptors that recognise iron-loaded transferrin and allow them to take that iron inside. Once there, iron can be used OR stored as ferritin. Now we finally meet the marker everybody has been talking about.
Ready for part 2 on your iron larder? Subscribe to our newsletter HERE, so you don’t miss out on the news.
To health!
From the team at the New School of Nutritional Medicine.
