Iron metabolism, explained

Should you read or remember only ONE thing from this piece, it should be the following ::

Iron is both ESSENTIAL and TOXIC to the human body.

In a society where most people seem to think “if a little is good, than moore must be better” I truly wish to place emphasis on the fact that this motto cannot be applied to most of our metabolic needs and processes.

Version FRANÇAISE ici.

The human body was created to constantly and tirelessly dissipate the excesses and insufficiencies that our chosen lifestyles generate. Why in the name of Life anyone would aim to overburden such a beautiful machine is beyond me?!

Isolated iron supplementation should be done using a “Goldielocks” approach; it is not recommended to all and the guidance of a health care professional is very much advised.

Notoriously hard to absorb, iron is also pretty hard to get rid of. A poorly informed, “self-supplementation regimen” could place a well-meaning individual in a deleterious state of overconsumption and absorption.

Iron has many uses within the body ::

• Oxygen transport
• Electron transfers
• Cellular respiration –> energy production!
• Synthesis and repair of DNA and various proteins
• RNA synthesis
• It is a cofactor of numerous enzymes :: enzymes which are essential to ALL human biochemical reactions
• Necessary to the production of hemoproteins :: hemoglobin, myoglobin, cytochromes…

When in excess and/or in a case of compromised regulation, it can disrupt wellbeing ::

• It promotes the formation of ROS, Reactive Oxygen Species. These molecules can cause damage to DNA and/or inactivate certain enzymes. In simple terms, think :: toxic free radicals. Poorly regulated and/or excessive circulating iron levels can cause premature, accelerated cell aging. (Fenton’s reagant)

This important mise-en-garde out of the way, we can now discuss how the human body regulates its iron supplies.

Intakes

Iron is a mineral that is deemed “essential” :: the body cannot produce it therefore, dietary sources must be consumed.

There are 2 forms of iron available in food ::

**An important distinction vegetarians and vegans will want to pay attention to :: absorption pathways of these 2 minerals are different, and the quantities absorbed are not the same either.

• Ferrous Iron/ Fe²⁺/ heme iron :: Makes up 10% of dietary iron and represents 1/3 of all absorbed iron. This form comes from animal sources which package the mineral in hemoglobin and myoglobin that is similar to ours. “Heme iron” confirms that the iron is located within a heme protein. We could compare this type of iron to a guy (iron) arriving at the public pool (human bloodstream) wearing a jacket (heme) on top of his bathing suit. Stick with me, I hope this makes things clearer for us later!  😉
• Ferric iron/ Fe³⁺/ Non heme iron :: Makes up about 90% of dietary iron and represents 2/3 of all absorbed iron. This inorganic form mainly comes from plant sources. It is not packaged in heme it is more like a swimmer arriving at the public pool buck naked! No coat, no bathing suit! I’m sure you see why SOME alterations will have to happen to this guy before he can gain access to our blood pool.

Absorption of NON heme Fe³⁺ iron :: the one that requires vitamin C

In the intestinal tract, ferric iron from plant sources cannot “simply” be absorbed; an enzyme must first alter its charge, that little number floating at the top right of the Fe (enzyme DCYTB, mainly). This enzyme requires vitamin C to operate. If you’ve ever heard that it’s beneficial to combine plant iron sources with vitamin C rich foods :: this is why!

NO vitamin C means NO charge alteration which in turn means NO absorption

If we go back to our dodgy analogy, this “charge alteration” is a bit like asking naked guy to put on a suit before entering the premises. Entrance is therefore conditional to 2 criteria :: 1 – having the ability to get dressed, the enzyme and 2- having a bathing suit on hand, vitamin C.

*It is worth mentioning that adequate stomach acid (low pH) also plays a role in the alteration charge of iron. People on proton pump inhibiting medication, which reduce gastric acid (up the pH), should keep this is mind when evaluating their needs¹. H. pylori bacteria is also known to throw off our ability to absorb iron through its pH rising effect on stomach secretions².

Fe³⁺ iron now converted into Fe²⁺ -our naked bather in appropriate public pool attire- can travel form the intestines into intestinal cells via transporters/ doors (DMT1). 

Iron being highly reactive and actually damaging to the human body in its free form; it can only be allowed to travel from the intestinal cell into circulation once coupled with a “stabilising/ disarming/ mitigating” molecule ::

• For its circulation out of the intestinal cell into the bloodstream :: transferrin is in charge, it is a transport or transfer protein.
• For its storage inside our cells :: it gets bound to ferritin, an iron reserve protein

Once again, iron’s charge will have to be altered. Iron cannot bind to neither transferrin or ferritin in its newly acquired Fe²⁺ form. Our naked swimmer might be wearing a suit now, but he will not gain access to the water unless he’s wearing the mandatory bathing cap.

Iron assimilation :: a copper dependant step

• Hephaestin :: who’s main job is to facilitate the iron’s exit from the intestinal cell where it was absorbed initially
• Ceruloplasmin :: which is in charge of facilitating iron’s binding to transferrin for its safe blood transport

These 2 components partly explain why genes that are implicated in copper regulation react similarly to those regulating iron in a deficiency situation³.

Recap ::

1. Iron from plant sources must have its charge altered in order to gain access to intestinal cells. An enzyme, with vitamin C’s help, is in charge of converting Fe³⁺ iron into Fe²⁺iron. We can imagine a naked person wanting to gain access to a public pool, the charge altering can be imagined as a change into proper, non-naked attire.
2. Iron, now in its “bathing suit form”, enters the cell via a transporter.
3. To gain access to the bloodstream and ultimately be used or stored iron must, for the second time, have its charge altered. Our swimming enthusiast must now put on his bathing cap before he can dip his toe in the water. Hephaestin and ceruloplasmin, 2 proteins that rely on copper, are in charge of this step.
4. Iron is now perfectly configured to be used by the body however it pleases.  

It is logical to conclude that overconsumption of iron via dietary PLANT sources is highly improbable (NOT talking about supplements here!). This complex mechanism has a protective effect on our constitution :: plant iron being a common occurrence, its complete and full absorption at all times could have harmful effects.

Absorption of heme/ Fe²⁺ iron :: no vitamin C required!

Iron form animal sources comes already with the charge required for intestinal absorption :: he’s just that decent guy who arrives at the pool ALREADY wearing a bathing suit. This type of iron simply uses a transporter to get into our cells (HPC1). Both types of iron have their own specific transporters and that is a good thing because it means there is no competition for the entryway. A public pool has more than one door, and each bather has its fave. There, no fighting!

Once Fe²⁺iron is inside the intestinal cell, an enzyme, heme oxygenase, proceeds to free it from its heme packaging. Still going with our pool/ bathers’ analogy, then “enzyme & heme” combo would best be represented by a jacket (heme) that one would leave in a locker (enzyme). Our iron, guy coat free and in his swimming trunks is ready to go and will then follow the same steps as the other form of iron previously described :: bathing cap/ copper dependence, proteins to keep it safe within the bloodstream…

As we can see, both forms become interchangeable once the initial absorption is over. Bathing suit? Check. Coat left in the locker? Check. From that point on everyone can act the same :: put your bathing cap on and proceed. Charges are altered following the body’s cues, both iron forms able to go from the “stored” form to the “use up” form with the help of enzymes and copper dependant carrier proteins.

Regulation

Intestinal cells will only “activate” their iron receptors if they have received a signal to do so. The number of receptors on the cells’ surface is not static but fluctuating in accordance with hormonal messaging^4,5.

It is hepcidin, liver hormone master of iron regulation, who’s in charge of communicating metabolic needs to all the parts involved in iron absorption and circulation.

• When iron is sufficient or overabundant :: hepcidin binds to ferroportin; the one known iron exporter which is located on the cells’ surface. Hepcidin causes internalisation and degradation of said iron exit doors. It sequesters iron INSIDE the cells by burning all the bridges giving it access to our circulatory system and tissues in order to limit its use and accumulation and prevent an adverse outcome.

Not only does it imprison iron inside storage cells, hepcidin also blocks intestinal absorption; hepcidin secretion is increased when iron is sufficient or overabundant.

Inversely, an inadequate iron pool will cause a decrease in hepcidin secretion, allowing unrestricted intestinal uptake and improved liberation of stored iron for usage.

Worth mentioning :: An infectious and/or pro-inflammatory state has a promoting effect on hepcidin. Iron regulation is therefore not ONLY an “iron in/ iron out” mechanism. Acute or chronic inflammation plays an important role on proper iron regulation via its effect on hepcidin. Obesity, auto-immune conditions, pathologies involving chronic blood loss and/or constant irritation of the intestinal mucosa, pregnancy, H. pylori infection… All of these conditions have some type of direct or indirect effect on an individual’s iron stores.

Iron recycling

There is NO known active iron excretion mechanism in humans. Iron that is present in the body is primarily regulated via intestinal absorption modulation; it is increased at times and slowed or stopped during others.

This regulation can be described as “self-sufficient”; it requires very little iron entry or excretion since it is constantly being reused/ recycled.

Of the 3 to 5g of iron present in a healthy body, 99% will never find the exit; explaining why we have such minimal daily dietary requirements.

Within the body, iron is distributed in these ways ::

• Production and maturation of red blood cells and their precursors in the bone marrow “hog” 2/3 of all iron stores; the majority of which comes from the recycling of red blood cells that had reached the end of their useful lifespan. Macrophages from the spleen and liver are in charge of red blood cell degradation and recirculation of their useful components.  
• A fraction of available iron is stored as “ferritin” within liver cells.

Longevity

Contrary to what one might think, the total concentration of iron within the body tends to increase with the years⁶; the average North American diet frequently providing more than is necessary. This accumulation is thought to be partly responsible for premature or accelerated cell aging due to the oxidative stress it generates. A few studies have shown iron deposits within the brain’s dark matter (substantia nigra) of individuals suffering from Parkinson‘s disease⁷. 

A lesser concentration of iron such as the one usually found in women who menstruate, could partially explain why feminine longevity is greater than men’s. Periodic, monthly bleeding representing regular iron losses; it could possibly have a preventative effect on excessive iron concentrations. Dr Thomas Perls‘ research work on this topic (and longevity in general) is particularly interesting. 

More and more studies seem to define vegetarian sources of iron as “protective” from this accumulation phenomenon; despite an abundance of iron in the veg diet, the absorption rate remains modest. What we assumed just a few years ago to be a “miss” for vegetarians is slowly turning out to be an advantageous, built-in regulation system that brings benefits in the long run for those consuming an adequate, properly planned, plant rich diet^8,9.

Dietary sources BEFORE supplementation

I’ll say it one more time :: isolated iron supplementation is not a thing to be done haphazardly; a blood test is one of the great tools when evaluating your needs. Worried? Curious? A simple blood draw prescription from your MD is an excellent way to begin your investigation.

That being said, the values from a blood analysis are only one piece of the puzzle :: your dietary choices, your general state of vitality and other lifestyle particularities are invaluable tools in the comprehension of your specific needs.

If you wish to know more about the implications of chronic sub-optimal iron intakes, maybe you’ll enjoy reading this piece on anemia.

All bits influencing all parts at all times within our bodies, it is foundational to understand that iron does not work alone. vitamin C and copper were mentioned here but B6, B9 and B12, among others, are also of capital importance on the journey towards proper iron metabolism, abundant energy and deep-rooted wellbeing.

The « VBN Sheet – Iron » sheds light on all basic facts about this important mineral :: daily reference intakes, sources, possible losses and risks linked to overdoing it are all discussed there.

A few studies have been linked through this article, get acquainted with the data if you wish to know more about this topic; this post is merely a quick introduction, a simplified intro into the subject. 

Research papers are always a great way to approach a discussion with your health care provider, feel free to share them with yours if you feel it would be useful in the evaluation of your specific needs and the enhancement of your vitality. 

Stay curious and humble, 

Be well,

Vicky x 

Vicky Bachand ND.A is a naturopath :: a naturopath does NOT replace a medical doctor. 

Ideas provided in this article are presented as information only and do not aim to provide in depth details about the chosen topic nor replace the advice of a qualified health care provider. 

Information shared here does not constitute a consultation, a diagnosis nor a medical opinion and therefore should not be interpreted as such.

Always consult with your chosen health care provider if you have questions about your personal health.