We wrote in a recent post about functional laboratory testing for anemia. Different forms of anemia result from many different causes, and iron deficiency anemia is the most common form. In this post we're going to expand on iron dysregulation and some other sequelae of iron deficiency. We'll also get into markers for iron status that weren't covered in the anemia post, so keep reading to learn more!
Most of the iron in the body is found in hemoglobin, which is utilized by RBCs to make oxygen transport possible. Much of the remaining iron not utilized by hemoglobin is bound by proteins like transferrin and ferritin because free iron must be tightly regulated to prevent damage. Free iron is extremely reactive and can also be utilized by pathogenic bacteria to proliferate (1).
In this post we'll go into more detail about iron status markers and iron deficiency, whereas in the previous post on anemia we concentrated more on the RBC section of the CBC. We'll be focusing on the other side of the coin, iron overload, in an upcoming post. To learn more about how to evaluate iron status and identify iron deficiency, keep reading! We'll talk about several iron markers, including ferritin, transferrin, serum iron, TIBC, UIBC and iron saturation.
Roles of iron in the body
Let's begin by talking about how the body utilizes iron in more detail. In our previous post about anemia, we wrote about iron deficiency anemia, which is one of the main consequences of iron deficiency. Other sequelae of iron deficiency we'll discuss here include heart issues; dry, damaged skin and hair; restless leg syndrome; pica and brittle or spoon-shaped fingernails. Many of these symptoms result from inadequate oxygenation, and as we'll see from a study we'll get to shortly, iron deficiency symptoms can be present even without a diagnosis of anemia.
Nitric oxide production is iron-dependent
In addition to negatively impacting the body's ability to transport oxygen, iron deficiency also reduces the body's ability to synthesize nitric oxide (NO), which dilates blood vessels. Iron is a necessary cofactor for NO synthesis, so iron deficiency impairs blood vessel dilation is impaired. It's not just that oxygen can't be transported, it's that the flow of blood to peripheral tissues is also impaired due to a lack of NO (2).
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Iron necessary for liver detoxification
Iron is not just limited to oxygen transport and utilization. Iron is also a critical nutrient for the function of many cytochrome enzymes, including cytochrome P450 enzymes that are responsible for liver detoxification (2). Consequently, iron deficiency can downregulate phase 1 liver detoxification. Iron also relates to thyroid health, which we wrote about several months ago in a post on Hashimoto's thyroiditis.
Peroxidase enzymes need iron
Thyroid peroxidase enzyme (TPO) synthesizes thyroid hormone and is dependent on iron. Consequently, thyroid hormone production may fall in iron deficiency. TPO uses hydrogen peroxide (H2O2) to ready iodine for thyroid hormone production. Myeloperoxidase (MPO) is another iron-dependent peroxidase enzyme that controls pathogenic bacteria by producing sodium hypochlorite (NaClO), or bleach, from hydrogen peroxide in order to kill pathogens. MPO malfunction can lead to immune function failure, gut infections and dysbiosis.
Catalase is a third iron-dependent enzyme. It converts hydrogen peroxide (H2O2) to water in order to control levels of H2O2 and prevent cellular and metabolic damage. Free iron that is not bound by a protein can be particularly destructive in the presence of H2O2, with which it can interact to produce dangerous hydroxyl radicals (OH), which causes more damage than just H2O2 or free iron alone (3). It's easy to see from these examples how far-reaching the roles of iron are.
Like many nutrients, there is a sweet spot for iron levels, and this is doubly true given its role in many metabolic processes, as well as its potential to cause damage. Next we'll discuss the context of iron deficiency anemia in the larger picture of health before moving on to heme vs non heme iron and some other nutrients required to utilize iron properly.
Anemia is priority
Let's pause for a second, zoom out and reorient ourselves in the larger picture of health. In challenging patients it can be tempting to sometimes deprioritize anemia and focus on what may appear to be more pressing concerns. Although there may be situations where this is necessary, they are generally few and far between, especially in the chronic disease world. Because nearly every biochemical process in the body is energy dependent - that is - requires ATP, anemia affects every cell with mitochondria and every system in the body.
For this reason it's often advisable to get the anemia patterns straightened out early on, before moving on to other areas of treatment, unless there is a good reason to start somewhere else first. With that bigger picture in mind, let's zoom back in and review the importance of heme vs non-heme iron.
Heme vs non-heme iron
One big determining factor for iron intake is the form of iron an individual is consuming. Non-heme iron from vegetarian sources is poorly absorbed and utilized compared to heme iron in meat, especially red meat. This can be an issue for long-term vegans and strict vegetarians, especially those who do not eat any shellfish, which are also a good source of heme iron. Non-heme iron is typically present in an oxidized form, whereas iron needs to be in its reduced form in order to be absorbed (4).
Other factors that affect iron absorption include vitamin C, which increases absorption of non-heme iron by reducing it into more absorbable form (5). Vegetarians who want to increase absorption of plant-based non-heme iron can try consuming with Vitamin C with food. On the other hand, plant foods contain phytates and polyphenols that inhibit iron absorption, so properly soaking seeds and grains before eating is also important to maximize iron absorption.
Calcium also blocks absorption of iron, so calcium-rich foods like spinach and dairy may reduce absorption of iron from iron-rich foods (6). To raise iron levels, concentrate on isolating calcium-rich foods to one meal per day and have another meal that is rich in iron foods like red meat, liver and clams. Now that we've covered these factors affecting iron absorption, we'll next discuss the role copper and vitamin B6 play in iron regulation.
Vitamin B6 and copper
Vitamin B6 and copper affect the body's ability to absorb and utilize iron. B6 in particular is required to absorb iron. One study on anemic pregnant women treated with iron supplements found that the women who did not initially improve were deficient in B6 and after adding B6 to the iron supplement, anemia improved (7). In addition, both B6 and copper are involved in the utilization of iron to synthesize RBCs.
Copper has a complicated relationship with iron. On the one hand, copper can impede iron absorption by binding to mucosal transferrin at the expense of iron, and excess copper inhibits the ability of spleen reticuloendothelial cells to reuse iron (8). On the other hand, copper is also needed to mobilize sequestered iron from storage tissues. Similar to B6, this can lead to a form of anemia that does not respond to iron supplementation unless copper is also added (9).
It can be worth looking at B6 and copper status and intake in cases of anemia, especially if there are other clues present. Other indicators that copper and B6 may be involved are mood and temperament issues. B6, copper and zinc are required for neurotransmitter synthesis and zinc/copper balance can contribute to aggressive behavior, deficiencies or imbalances in these nutrients may manifest as symptoms of mood, anxiety or temperament (10).
High levels of zinc supplementation for prolonged periods of time without copper supplementation can lead to copper deficiency. This is worth noting for people who supplement with zinc.
Next we'll talk a bit more about iron deficiency before moving on to related laboratory markers.
Iron deficiency is the most common nutritional deficiency worldwide (11). The most prominent consequence of iron deficiency is iron deficiency anemia, which is also the most common form of anemia. Iron deficiency reduces the ability's body to transport oxygen via iron-containing hemoglobin on RBCs and results in classic anemia symptoms like fatigue, shortness of breath, pale skin and brittle nails.
Although iron deficiency anemia is the main consequence of deficiency, it's not the only one. We mentioned a study in the introduction about non-anemic iron deficiency. It found that in a population of 198 menstruating women with low ferritin but normal hemoglobin, oral iron supplementation improved fatigue symptoms (12).
Other iron deficiency issues can include:
- Heart abnormalities like irregular heartbeat, heart palpitations, and in extreme cases enlarged heart, heart murmur or failure
- When cells are starved of oxygen, the heart must work harder to circulate more RBCs because they can't carry much oxygen
- Compounding the issue, the heart itself may lack sufficient oxygen for muscle contractions
- Dry, damaged skin or hair (13)
- In a mouse model, reversal of iron deficiency led to a restoration of hair growth
- Iron deficiency may contribute to hair loss by inhibiting the iron-dependent ribonucleotide reductase enzyme, which is a rate-limiting enzyme for DNA synthesis
- Hair and skin cell lines both turn over rapidly
- Restless leg syndrome (RLS)
- Pica is a condition of craving or eating dirt
- It can result from many causes, some psychological
- Iron deficiency pica is characterized by a compulsion to consume iron-containing substances like clay, soil and even small rusty pieces of steel
- Pagophagia (pica for ice) may also indicate iron deficiency (16)
Because iron plays a central role in transporting and utilizing oxygen to produce ATP, it's important to resolve iron deficiency and anemia early on in care. Countless critical processes in the body are energy dependent, and if cells are starved for energy they are not going to function properly. In this way, iron deficiency can be central to many diverse health conditions. Next, let's shift gears and talk in more detail about iron status markers.
Iron status markers
In addition to the anemia markers on the CBC we discussed in our previous post, iron status markers are helpful in cases of suspected iron deficiency anemia or iron overload. In this section we'll go into more detail about each of the markers and how to use them clinically. As we mentioned earlier, iron is tightly regulated by the body because of its massive reactive potential and the ability of pathogens to use iron to their advantage (17).
In addition, the body has no way to eliminate excess iron other than bleeding and menstruation, so iron status is dependent on two factors - dietary iron intake coupled with how iron is utilized and stored in the body. As mentioned previously, the body strives to keep most iron either in use in hemoglobin or bound to proteins like transferrin and ferritin to prevent free iron ions from creating oxidative stress and encouraging the proliferation of pathogenic bacteria.
With anemia we are looking primarily at cells - RBCs and their components like hemoglobin. These markers are found on a standard CBC.In contrast, the markers on a complete iron panel are not part of a CBC and must be ordered separately to confirm or rule out suspected iron deficiency or overload. We'll get into each of these iron panel markers in more detail now, as well as a few other markers that can be relevant.
Ferritin: our preferred functional range is 50-150 ng/ml* (Iron Disorders Institute prefers 25-75 ng/ml for those with hereditary hemochromatosis and for anyone levels above 100 ng/ml may indicate an increased disease risk*)
Iron is bound to ferritin to create iron stores in tissues including the liver, spleen and bone marrow. Depressed ferritin may indicate iron depletion, but many factors can affect ferritin and it's best to view it in the context of a full iron panel. Ferritin sequesters iron in long-term storage to prevent free iron from causing oxidative stress and to make it unavailable to pathogens which will use it for their own growth.
Ferritin on its own without other markers for context can be misleading, as several factors such as oxidative stress and inflammation can elevate ferritin levels. Inflammation can mask iron deficiency and result in a false normal ferritin level. Inflammation can be confirmed by running hsCRP, which we'll talk about shortly.
Other possible influences on ferritin levels include intake of sulfuraphane (18), milk thistle (19) and green tea extract (20), which can all upregulate ferritin. These products can also lead to anemia by causing the body to store more iron and diverting it away from hemoglobin. Ferritin is also elevated in liver damage, hemochromatosis, neurodegenerative diseases and in response to inflammation.
As we can see, ferritin is impacted by many factors. It also has antioxidant properties, and factors that increase synthesis of glutathione and catalase also increase ferritin because it's part of the antioxidant defense system (21). Because many biochemical causes can impact ferritin and potentially cancel each other out, it is important to view ferritin in the context of other markers on a complete iron panel, which we will discuss now.
* Cardiovascular and blood sugar disease risk increases with ferritin levels above 100 ng/ml. However, these risks can be mitigated with properly functioning antioxidant defense mechanisms. With properly functioning antioxidant defense, levels of 150 ng/ml or above may be safe.
The protein transferrin is largely synthesized in the liver and binds iron for transportation through the blood. In addition to binding iron for transport, transferrin is a major component of iron regulation primarily found in the blood and tissue fluids (22).
Serum transferrin is a somewhat expensive test. We sometimes order TIBC instead, which we'll talk about shortly, as TIBC can be an indicator of transferrin status. Other factors influencing transferrin include liver disease, which can reduce synthesis, and dietary iron. Transferrin can vary considerably based on the iron content of a person's last meal, so it needs to be performed with the patient fasting.
This is simply the amount of iron in the bloodstream bound to transferrin. It is not the most reliable marker of iron deficiency but it's a better marker for iron overload like hemochromatosis, especially when combined with iron saturation. We'll talk more about hemochromatosis in an upcoming post.
TIBC: our preferred functional range is 275-430 ug/dL
Total iron binding capacity (TIBC) measures ability of RBCs to bind to transferrin. TIBC is elevated in iron deficiency, pregnancy and blood loss, and it's normal in anemia of chronic disease and inflammation. TIBC is depressed in elevated iron loads, liver disease, hypoproteinemia, infection and chronic disease.
UIBC, or unbound iron binding capacity, has an optimal range of 175-350 ug/dL. Lower levels mean higher iron.
Transferrin saturation: our preferred functional range is 17-45% with optimal being 25-35%
Elevated transferrin saturation (TS) stimulates hepcidin, which we'll talk about next. In turn, hepcidin downregulates iron absorption and increases storage of iron in ferritin. TS is more sensitive than ferritin because TS is what causes ferritin to increase in response to high iron. It's also more specific to iron status than ferritin, which is influenced by many other factors like inflammation, which we discussed earlier.
Hemoglobin is the iron-containing portion of a red blood cell that transports ozxygen from lungs to tissues. Depleted or excessive amounts of hemoglobin can point to imbalanced iron levels.
Mean Corpuscular Volume (MCV):
MCV is a measure of the average volume of red blood cells. Anemias are often referred to in reference to the size of the red blood cell. There is microcytic anemia (low MCV and often is caused by low iron), normocytic anemia (normal MCV), and macrocytic anemia (high MCV - also called pernicious anemia - often caused by low B12 and/or folate levels).
Gamma Glutamyl Tranferase (GGT):
GGT is a liver enzyme that has traditionally been used to primarily look for liver issues. Recently, it has become clear that GGT elevation (even high-normal values) can be associated with increased risk for metabolic syndrome. Levels greater than the lowest 25% of the population are associated with metabolic abnormalities, cardiovascular disease risk, and more.
Sometimes referred to as "The Iron Regulatory Hormone," hepcidin is the master coordinator of iron. High iron hepcidin downregulates iron absorption and directs free iron to be sequestered in ferritin. Hepcidin responds to threats like an infection via inflammation which could use free iron for its own proliferation. Hepcidin also has antimicrobial properties; in fact its name comes from the its location of synthesis, the liver (hep-), and its antimicrobial effects (-cidin) (23).
hsCRP: our functional range is 0-1 mg/L
We talked about hsCRP and inflammation earlier. Inflammation, as measured by high sensitivity C-Reactive Protein (hsCRP) can lead to false normal or even elevated ferritin in the presence of anemia. Anemia of chronic disease results in low absorption and high storage as ferritin, so high ferritin and iron deficiency can exist simultaneously because the small amount of iron that is absorbed is directed into storage instead of hemoglobin synthesis in an effort to sequester it away from pathogenic invaders. hsCRP isn't an iron marker per se, but it can be useful to confirm or rule out inflammation that may be elevating ferritin.
Now that we have a better understanding of these markers and how to use them to evaluate iron deficiency, let's review some iron-rich foods before closing. Also be sure to keep an eye out for our upcoming post on iron overload and hemochromatosis.
- Liver / organ meat
- Red meat - lamb, beef
- Blackstrap molasses
Iron is a critical nutrient and iron is the most common deficiency worldwide. Furthermore, iron deficiency anemia is the most common form of anemia, and it impacts every cell of the body because of its role in ATP production. It's easy to see why resolving iron deficiency is a critical piece for anyone whom is affected by it. Stay tuned for an upcoming post on the other side of the coin from iron deficiency - iron overload and hemochromatosis!
For those low in iron, here are strategies that can help increase iron stores:
- Make sure low iron is based on lab testing, as iron can be toxic when in excessive quantities
- Increase iron containing foods (especially those with heme iron like animal products)
- Add vitamin C with meals (500-1000mg)
- Contain calcium-containing foods and/or supplements to 1 meal per day (calcium blocks iron absorption)
- Iron supplementation under the guidance of a functional medicine doctor / practitioner
- Stop donating blood temporarily until iron stores are back up
- Avoid chelating substances or protocols intended to chelate metals
- Be sure you re-test labs so that you know when levels are normal and you can simply maintain
- If you do not have success with basic practices, see a functional medicine doctor / practitioner to identify root cause issues that might be preventing iron absorption
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