The following discussion is a summary of what is known about the metabolism of iron. Some of this material is drawn from human research and is extrapolated to other species. All animal species that utilise oxygen as fuel for energy have incorporated the use of iron. Across all different species of organisms, the principles remain largely the same.
That said, research still needs to be done to further clarify how much iron is needed by the body and how the body maintains a balance of iron in the body for emergency use in addition to its everyday use. What is the result of extra iron in the diet? How much iron is too much iron?
This last question has been the subject of much heated debate within the horse industry as claims and counter claims are made. Some would argue that any extra iron in the diet i.e. more than 100% RDI could likely result in insulin resistance (IR). Others would claim that not only is there no absolute figure that defines excess, but there are probably no health issues resulting from ingesting “too much iron”.
An exception to this is the case of foals. Foals have died from liver toxicity from too much iron as a result of well-intentioned but misguided attempts to prevent anemia. Their immature gut system is designed to absorb animal protein in the form of milk and iron is absorbed more easily in newborn animals. Iron injections are also potentially risky to horses as they bypass the safety measures in the gut that inhibit excessive iron absorption into the blood stream.
The ‘Great Iron Controversy’ appear to originate from a study conducted by Dr. Brian Nielsen et al in 2012. The study was titled “A potential link between IR and iron overload in browsing rhinoceroses investigated through the use of an equine model” published in the Journal of Zoo and Wildlife Medicine in 2012. The name of the study is perhaps a little ambiguous, on one hand it could be interpreted that iron overload leads to IR whilst on the other hand, IR could lead to iron overload.
Dr Nielsen sought to clarify this in an online posting in April 2013. As quoted by Dr. Nielsen – “The point of our study was to see if the reason iron was accumulating in black rhinos was BECAUSE they were insulin resistant” (http://www.thehorse.com/articles/31737/insulin-resistance-and-iron-overload).
Still, the headlines became “Researchers identify link between Insulin resistance and Iron Overload” penned by various commentators. For those owners concerned about and frustrated by their own horses having IR this seemed like a way they could control the situation. This soon led to the advice that horses should receive no iron supplementation at all and that all feedstuffs should be tested for iron levels before being fed.
So, let us approach this issue armed with peer reviewed scientific knowledge and see what conclusions can be reached.
1. The behaviour of iron atoms and molecules within the body.
Experts are agreed that iron is essential for the survival of the body. It is needed in the transport of oxygen in the blood stream in the erythrocytes (red blood cells). Bacteria are also, dependent upon iron for their survival and this important fact is integral to how the body stores and releases iron.
Iron’s central purpose is to mediate electron transfer at the atomic and molecular level (oxidation and reduction reactions). Iron atoms are incorporated into protein molecules to facilitate enzyme reactions. Iron’s reactivity can also be a potential problem – its ability to donate and accept electrons means it can catalyse hydrogen peroxide into free radicals. Free radicals can cause damage to a wide variety of cellular tissues and can ultimately kill the cell. Iron bound to proteins or cofactors is safe. There are virtually no free iron atoms in the cell since they readily form complexes with proteins. Some of the iron is bound to low affinity complexes and this is termed labile or free iron. It is the iron in these complexes that can cause the damage to cellular structures.
Evolutionary pressures over eons of time have solved the cellular damage problem – all life forms that use iron bind the it to proteins. This allows the cell to benefit from the iron while greatly minimising its ability to do harm. Typically, in a mammalian cell more than 95% of the iron in the cell is bound to stable proteins. To label iron as” dangerous “because of its potential to form radicals is emotive language that questions the ability of the body to cope with this issue. To state that free ionised iron can produce a “chain reaction of destruction” is also an example of highly emotive language. Upon reading such a statement, many people will feel needlessly alarmed and very anxious.
Our advice is to be aware of the fact that iron has this potential under certain conditions, but also have confidence that the body has evolved safe and effective ways to deal with this potential issue.
2. Absorption, storage and elimination of iron in the body.
The body has developed sophisticated and effective methods to control iron intake in the body and to regulate its use and disposal. Iron metabolism is the set of chemical reactions maintaining homeostasis of iron at the cellular and systemic level.
A 500kg horse has approximately 33 grams of iron in its body – 60% of that iron is in the erythrocytes, 20% is in myoglobin in muscles, 20% is in storage and transport in the body and approximately 0.2% is in body enzyme systems. The liver’s store of ferritin is the primary physiologic source of reserve iron in the body. liver storage of iron can fluctuate within a defined level as needed by the body but iron in erythrocytes and enzyme molecules must be kept at a steady optimal level. Because of its potential toxicity, free soluble iron is kept in very low concentrations in the body.
Iron homeostasis in the body is regulated by two processes- systemic iron levels are balanced by the controlled absorption of dietary iron by enterocytes (cells lining the gut wall) and the uncontrolled loss of iron by enterocyte sloughing, sweat, injuries and blood loss e.g. parasitism and bleeding stomach ulcers. A heavily sweating horse can lose up to 500mg iron per day. Mares milk also has reduced iron levels as lactation continues. Systemic iron is continuously recycled by the body.
The absorption of dietary iron is a variable and dynamic process i.e. it is not at a constant level regardless of circumstances. It has the capacity to increase or decrease as needed. Absorption is typically, low-from 5% to 35% depending upon the source of iron and the need for it. Dietary iron absorption in horses is likely to be 15% or less. High levels of iron in soil and feed stuffs does not mean that all or even most of it is absorbed.
Dietary iron is absorbed by the cells lining the small intestine. The cells use specific iron binding transport proteins to move the iron from the gut into the cell. These cells can then either store the iron as ferritin where ferric iron is bound to apoferritin or it can be transported from the cell into the body by ferroportin. Should the enterocyte die and be sloughed into the manure the iron stored in the cell is lost to the body. The enterocyte in response to signals from the liver can increase the amount of ferroportin molecules to increase release of iron from the cell to the body. Iron absorption can also be diminished by the presence of high levels of calcium, zinc and manganese in the diet.
Possible other sources of iron absorption are through volatile fatty acids fermented in the gut- more research needs to be done if this so and the mechanisms by which they operate. Iron may also pass passively through intercellular spaces- under what circumstances does this occur and what percentage is absorbed this way? These are questions that need further research. The general consensus is that by far the majority of iron is absorbed by enterocytes as previously outlined. The body needs a strictly regulated mechanism to control absorption as it cannot afford to have free iron ions circulating unimpeded throughout the body.
The body’s rate of iron absorption appears to respond to a variety of interdependent factors including total iron stores, rate of new erythrocyte production, concentration of haemoglobin in the blood, and the oxygen content of the blood. To suggest that other absorption pathways are unregulated hints at the body being effectively unable to protect itself. There are no scientific peer reviewed studies that prove that this is the case.
The body also absorbs less iron during times of inflammation. This will be discussed in due course.
Most of the iron in the body is stored and recycled by the reticuloendothelial system which breaks down aged erythrocytes. There is no physiologic system that regulates the excretion of iron. In the presence of an efficient and effective absorption control system and carefully regulated use of stored iron the body has not needed to evolve a system of active iron excretion as with other minerals e.g. sodium, potassium, magnesium etc. To put this fact forward as suggesting that the body will just keep on adding iron to its stores is misleading.
Cellular Iron level regulation
Most cell types take up iron through receptor mediated endocytosis through highly specific and controlled enzymatic reactions. It can also enter via plasma membrane divalent cation importers. Neither of these processes are passive transporters of iron from the extracellular site to the intracellular site.
Iron can be stored in ferritin as ferric iron (Fe 3+) which then awaits its future use. Dysfunctional ferritin accumulates as haemosiderin- a chemical that results from iron overload. The ferritin storage pool of iron is much larger than the labile iron pool.
Ferroportin is the only known enzyme that transports ferrous iron (Fe2+) out of the cell. The ferrous iron is then converted to ferric iron to be transported elsewhere. This need to convert iron into its different forms is another safeguard from uncontrolled oxidative reactions that could harm cells.
Hepcidin is an enzyme released from the liver that decreases release of iron from storage in the cell. The expression of hepcidin is tightly controlled and represents the link between cellular and systemic iron homeostasis. It is the gatekeeper that controls the release of iron from enterocytes into the rest of the body. In the case of an iron deficiency the cells actively hold onto their iron preventing the unnecessary synthesis of iron storage proteins and the export of iron from the cell. In summation, there are many enzyme and feedback systems that accurately control iron metabolism for the benefit of the body. It is a highly efficient and sophisticated system designed for survival.
Pathology of iron storage and usage.
When a healthy functioning body becomes diseased, there will be changes noticed in the functioning of the liver. Veterinary pathologists may tell you they see “a lot of’ diseased horse livers”. Their very job description means they are almost always investigating diseased animals.
Pictures of diseased, cirrhotic, blackened livers as evidence of iron toxicity without any contextual detail of that individuals’ history of iron ingestion, concurrent metabolic pathology, duration of illness etc. is frightening and causes anxiety in people who don’t understand the many questions that need to be answered before an explanation can be reached.
Whilst rare in horses, should it occur, it can be due to any of the following factors:
- Increased demand for iron which the diet cannot supply.
- Increased loss of iron through blood loss.
- Nutritional deficiency due to a lack of dietary iron or dietary components that inhibit absorption.
- Inability to absorb iron.
- Damage to the intestinal lining that reduces the surface area available for absorption.
- Inflammation leading to hepcidin induced restriction of iron release.
- It may occur in response to an extraordinary ingestion of iron in the diet that damages the lining of the gut and compromises its ability to regulate iron uptake. Horses that raid feed sheds and eat a large amount of an iron supplement in one sitting might possibly suffer iron overload.
- An acute overload of iron can become iron toxicity where the bodies homeostatic mechanisms are overwhelmed to the point where cardiac, liver, renal and brain function are severely compromised. This can result in death. This is most likely the issue that young foals deal with when given iron way in excess of what they need.
- Chronic iron toxicity or overload can also be the result of genetic conditions- especially in humans.
- Chronic inflammatory conditions may also lead to iron overload through reduced release of iron from storage. The body evolved to deal not only with normal day to day metabolic processes but also to deal with infections caused by bacteria, viruses, spores etc.
Inflammation and iron storage
Most bacteria also use iron in their metabolic pathways. When the body detects a bacterial infectious process, it reacts by immediately reducing available iron which the bacteria needs to continue to multiply. This is in addition to the other protective responses that come into play. In the short term, the body greatly reduces iron absorption from the gut and also shuts down release from iron storage cells. It is an attempt to starve the bacteria of the iron they need. When the infection has resolved the body returns to its normal processes to harmonise iron homeostasis.
While bacterial invasion is an infectious inflammatory response, there are other occasions within the body where noninfectious inflammatory conditions result. These can include cancer, endocrine disturbances, metabolic diseases, laminitis and autoimmune diseases. The body may not be able to differentiate between the different causes of inflammation but it still sets up the standard response i.e. reduce iron availability to the inflamed tissue. Long term this could lead to build up of iron in the liver SECONDARY to another predisposing cause.
Dr. Nielsen refers to this in his study of black rhinos with IR. “There is NO good evidence that feeding a diet low in iron will correct IR and conversely that excess dietary iron will contribute to IR “.
It would appear that some commentators are blaming iron as the culprit in IR. In fact, the most likely cause of IR is feeding too many calories of the wrong kind i.e. too many sugars and grains combined with inadequate exercise. Chronic iron overload then becomes the symptom of a primary problem initiated by other factors.
Modern lifestyles are increasingly being targeted as responsible for IR in humans, cats, horses, rhinos and possibly some other captive species in zoos as well. Too many calories, too little exercise and stress induced by boredom and frustration in the case of captive animals may all combine to cause this progressive, debilitating and chronic condition. Look to the real needs of horses in terms of dietary intake – ad lib roughage at all times and feed as little grain fed as possible. Ensure that there are adequate and appropriate levels of exercise and mental stimulation for a feeling of wellbeing. Be aware of breed differences that make some equines super-efficient at absorbing calories and also needing more exercise. Horse also need equine companionship and to be able to express natural behaviours.
Iron overload in humans.
There are studies that potentially link IR with iron overload in humans. These studies are directed at human populations that have genetic conditions that intrinsically alter normal iron metabolism. An example of this is thalassaemia- it presents as anaemia and repeated blood transfusions are part of the treatment protocol. The repeated transfusions lead to iron overload and this causes damage to the heart, liver and endocrine systems. Haemachromatosis is an abnormal iron storage disease of humans that results in liver steatosis and pathology. It would not seem reasonable to extrapolate these findings to horses who would have uniquely different causes for IR.
An unpublished paper authored by Dr. E Kellen summarised the following- ” Animals on mineral balanced diets had normal TSI and ferritin levels, and improvement in their insulin resistance, but since other measures were undertaken concurrently (e.g. reduction of NSC in the diet) the effect of mineral balancing per se` COULD not be determined”.
As more research is conducted and more evidence comes to light there may need to be a shift in the way iron supplementation is perceived. To date there has been no overwhelming evidence from multiple studies to suggest that horses are being deleteriously affected by the addition of supplemental levels of iron in the diet. The consensus of scientific opinion is that the increasing numbers of horses and ponies with IR is the result of genetics and modern feeding and husbandry methods. The role that iron probably plays in all of this needs further research but is in all likelihood the RESULT of abnormal metabolism rather than the primary problem.
IR is increasingly impacting the health of humans, horses and cats. The common factor across all three is the type of food being ingested i.e. too much sugars, starches and carbohydrates and less than optimal levels of exercise needed to keep the body healthy.
To study and look at iron in isolation from other minerals in the diet is also not appropriate. Iron levels will affect the rate of absorption of copper, zinc, calcium and manganese. This is why we have never believed in single mineral supplementation. We were the first Australian company to produce a product that contains ALL the necessary minerals in BALANCED ratios.
We at Equilibrium Australia are very aware of our responsibility to the horse industry to produce effective and above all safe nutritional supplements. We do not shy away from this responsibility and can confidently state that our products are safe, effective and can be use confidently used by horse owners and trainers. We have always advocated the Equilibrium Feeding Program which has always stated horses need good quality roughage at all times, as little grains and sugars as possible, and then balance their diet with vitamins and minerals that horse pastures and hays can be often deficient in.
Dr Lex Wills BVSc MACVSc observed the decline in horse health over the many years that he was an equine practitioner. Conventional treatments were either ineffective or only partially solved the problem. Horses were presenting with poor hoof quality, dull coats, infertility, colic, reduced performance, inability to put on weight, laminitis, and Seedy Toe just to name a few. At the same time the recommendations for feeding horses were drifting far away from what horses really needed to consume. There was a strong emphasis on grains and starches and less emphasis on good quality roughage. The resultant diets were mineral imbalanced and often deficient. The results of this change in feeding practice along with reduced exercise culminated in the range of medical issues that vets, owners and trainers were dealing with.
Dr. Lex Wills, through Equilibrium Mineral Mix and B1 Cool Mix began the discussion of how horses should be fed and supplemented with a broad-spectrum mineral and vitamin supplement. There are many, many, appreciative horse owners and happier healthier horses as a result of his genuine compassion and commitment toward improving the diet of horses.
Dr. Jenene Redding BVSc (Hons)