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Understanding Your Iron Group: What Results Mean for Each Biomarker

By Ashley Reaver, MS, RD, CSSD, July 23, 2020

iron sources

We're fully committed to providing you with a full view of your health and the tools to improve your biomarkers. This logic extends to the Iron Group, a collection of 11 different blood biomarkers that assess different characteristics of your body's iron status, from storage, to transport, to oxygen-carrying capacity, to the size and composition of your red blood cells. It is by far the most detailed group that we analyze from your blood results, and it's complicated! But true to our word, we're here to make it easier for you.

 

How does iron act in the body?

Iron is a trace mineral that our body requires each day. A trace mineral means that we require it in relatively small amounts, usually less than 5 grams per day. Although needed in only small amounts, trace minerals are anything but inconsequential. Other notable trace minerals include zinc, copper, chromium, selenium, and iodine.

Iron’s primary role in the body is oxygen transport. It is essential in the formation of hemoglobin, a protein found in red blood cells that transports oxygen from the lungs to every oxygen-requiring cell in the body. Iron is also is required for the formation of myoglobin, another oxygen-binding protein found in our muscle cells.

If you are reading this, you are breathing oxygen and, therefore, likely know that it's required for you to live. This is because oxygen is required during the final stage of energy metabolism to convert the energy that originates in food to the form of energy our cells can use. Without oxygen, our cells cannot convert the food you eat into the energy it provides. 

Some other notable functions of iron:

  • It’s required in at least two different steps in energy metabolism, outside of providing the oxygen for the final step
  • It’s a cofactor in the production of neurotransmitters, primarily those required for the developing brain of infants and children
  • It helps the immune system via production of natural killer cells. When iron is low, the likelihood of illness and severity of illness from infection increases
  • It’s also an integral part of a superfamily of enzymes collecting known as Cytochromes P450, which as involved in a huge range of reactions in the body, including drug and alcohol metabolism, cholesterol synthesis, sex hormone production, and the metabolism of vitamin D.

With all of these incredibly important functions, it is no wonder that people with low blood iron lack energy, feel lightheaded and foggy, and generally aren’t at their best. In this blog, we break down all of the markers in our Iron Group and explain their significance in iron’s function and on your health.New call-to-action

Ferritin is a storage form of iron and the best marker for iron metabolism 

Ferritin, in our opinion, is the best marker of iron metabolism. It is a storage protein for iron that is produced in the blood in response to iron in the diet. The more iron in the diet, the more ferritin, and the less iron in the diet, the less ferritin. It is found both in the intestinal cells responsible for absorbing iron from the diet and in the bloodstream. If the body has adequate iron, dietary iron gets trapped by the ferritin in the intestinal cells. And since intestinal cells have roughly a 2-5-day lifespan, the iron bound to ferritin there gets excreted when the intestinal cell is sloughed off at the end of its lifespan. This ensures blood iron levels don't go too high.

What causes high ferritin?

Excess dietary iron

This system of trapping iron in intestinal cells isn’t iron-clad. Excess iron in the diet can eventually overload intestinal ferritin and force its way into the blood, resulting in high levels ferritin in the blood. In the blood, ferritin binds to iron and releases it as needed to cells. It binds blood iron even if there isn't an excess of free iron in the blood—almost like a magnet. High ferritin can indicate an excess dietary iron, which can result in increased risk of iron deposits in the body’s soft tissues like the brain, organs, joints, and muscles—including the heart. This is one reason why high red meat intake is believed to be linked to higher risk of developing diabetes. Excess dietary iron intake can be deposited in the pancreas, impacting its ability to excrete insulin and control blood glucose levels.

Inflammation

When foreign invaders like bacteria and viruses are in the bloodstream, the body sequesters iron from the blood into ferritin, which the invaders can't infiltrate—since bacteria cells need iron to propagate, this helps to limit their growth and assault on the body. Of note: if you have an elevated ferritin level and elevated hsCRP, it’s likely that your ferritin is in some way falsely elevated due to inflammation. Read more about this relationship in our iron and inflammation blog. 

Hemochromatosis

This genetic condition causes an excess amount of iron to be absorbed from the small intestines. The mutation renders the mechanism that regulates iron absorption dysfunctional and prevents the body from getting rid of the excess. A person that carries the genetic trait from one or both of their parents can have elevated ferritin levels—and we’ve had a surprising number of InsideTracker users discover they carry this trait, due in part to high ferritin results! 

High ferritin is considered as greater than 200 ng/mL in women and greater than 300 ng/mL in men. To decrease levels, reduce dietary iron intake and consider donating blood regularly, especially if you are male.

What causes low ferritin?

Low dietary iron

Contrary to high ferritin, a low ferritin level indicates that you likely do not have enough iron in your diet. When dietary iron is low, the body doesn't need as much iron storage, and thus ferritin isn't produced as readily. Ferritin is also reduced in the intestinal cells to prevent iron from being trapped and lost there. 

Unlike some other iron markers, ferritin is a fairly consistent measure of iron status (other than during inflammation, see above), meaning it's unlikely to change based on one meal or supplement. Instead, it's based more on long-term iron status—sometimes changes in ferritin take weeks or months. The body's high requirement for iron makes maintaining storage difficult if adequate intake is not consistent.

Interestingly, the body also absorbs less iron the more it has. Similar to the law of diminishing returns, iron is absorbed at a high rate when needed, and at a much lower rate when it's not. Low levels of ferritin are often the first warning sign of developing anemia. For females, a ferritin of less than 11 ng/mL is considered low and for males a level less than 25 ng/mL is low. For active individuals, ferritin levels of less than 30 ng/mL may be indicative of low iron status. It's advised to take steps to increase ferritin before these dangerous low thresholds are reached. 

iron-1

Hemoglobin is the protein that enables red blood cells to transport oxygen

Hemoglobin is the protein on red blood cells that allows them to pick up and transfer oxygen from the lungs around the body. Red blood cells and hemoglobin are made in the bone marrow, which is found on the inside of long bones like the femur in the thigh and flat bones like those found in the hips. Hemoglobin isn’t complete without iron in the center, which enables them to carry four molecules of oxygen each. It's for this reason that inadequate iron reduces the oxygen-carrying capacity of hemoglobin.

What causes high hemoglobin?

  • High altitudes—At elevation, oxygen concentration in the air is sparse, so the body responds by producing more red blood cells, and, therefore more hemoglobin, to transfer better transport oxygen.
  • Medication—Some medications, like erythropoietin (EPO, the drug that eventually busted Lance Armstrong for doping) increase red blood cell production.
  • Polycythemia—A condition classified by high production of red blood cells, which can also cause high levels of hemoglobin.
  • Dehydration—Hemoglobin is measured as a concentration, so if your blood volume is low, hemoglobin levels can appear falsely high.

What causes low hemoglobin?

Low dietary iron

If ferritin levels are low, low hemoglobin is likely a result of inadequate iron in the diet—but only if inflammation levels are under control. If both are low, increasing iron intake will help to boost both ferritin and hemoglobin levels.

High blood volume

If ferritin levels are optimal and inflammation is low, low hemoglobin levels could be due to a change in blood volume, as it's measured as a concentration per deciliter of blood. If blood volume is expanded, then hemoglobin levels can appear low. Expanding blood volume is a physiological response in the body to a new workout regimen, increased ambient temperature, pregnancy, and overhydration.

One of the body’s first responses to a new workout routine is to produce more blood to meet the rising demands for fuel and oxygen throughout the body at a faster rate. Eventually, red blood cell production and hemoglobin catch up, but they can appear low initially.

An increase in temperature either from a change in seasons or a move can also cause blood volume to expand. The cardiovascular system diverts blood to the skin to release heat when body temperature rises. In an effort to pump more blood to the surface of the skin, the body will increase blood volume—and hemoglobin concentration may be diluted for some time.

One of the first responses to pregnancy in a woman’s body is to increase blood volume, which results in a dramatic decrease in measured hemoglobin concentration. This is normal, although levels remain less than “normal” for most pregnancies.

Lastly, overhydration can increase the amount of water in the blood and, therefore, increase its volume. Overhydration prior to a blood test can therefore cause this type of reading. If the cause of low hemoglobin is any of these, there is nothing to be done other than acknowledge the context around your blood results.

Genetic predisposition

There are some genetic predispositions that can result in lower levels of hemoglobin.[1] Sickle cell anemia, a mutation that causes C-shaped red blood cells, decreases the amount of hemoglobin that can be transported on a red blood cell. And while an individual with this condition is likely aware of it, there are other, less-obvious conditions that affect hemoglobin levels. Thalassemia, a family of mutations that cause decreased hemoglobin production, ranges from mild to severe effects (and treatments). Individuals from The Mediterranean, Middle East, and Northern African descent are more likely to experience thalassemia. Both of these diseases provide some resistance against malaria, which is why they are more common in areas where malaria exists.

Vitamin deficiency anemia

Lastly, low hemoglobin can result from anemia caused by the deficiency of other micronutrients like folate or vitamin B12, both of which are necessary for the production of red blood cells. Without adequate red blood cells, hemoglobin concentration will be low. Testing and correcting micronutrient deficiencies is necessary for increasing hemoglobin if this is the case.

 

Serum iron is a short-term measure of iron status

Iron, or serum iron, is the measure of iron in your blood at the time of the blood test. This iron can be influenced by food, especially fortified foods, or supplement close to your blood test. While it is a metric of iron status, it is less informative that ferritin for overall iron metabolism.

What causes high serum iron?

Excess dietary iron

Identify sources of iron in your diet, particularly supplements (including multivitamins), and fortified foods like cereals and protein powders. If you’re regularly consuming multiple high-iron sources, consider removing one or more of them from your diet.

Disease

In serious cases, it can also be the result of diseases of the liver or hemolytic anemia, when red blood cells are destroyed at a faster rate than they are produced. Hemolysis is the rupture of red blood cells, resulting in their contents, including iron, to be found in the blood.

What causes low serum iron?

  • Low dietary iron
  • Infection—When there is an invader in the blood, the body protects itself by removing free iron from the blood and binding it to ferritin where invaders cannot access it. (insert inflammation blog)

 

Transferrin saturation (TS) indicates iron transport around the body

Transferrin is the primary transporter of iron. Once iron passes from the intestinal cell to the blood, it is transferred to transferrin for shuttling around the body and distribution to cells. TS is a measured as a percentage—it’s the amount of serum iron divided by the total iron-binding capacity (more on that in a minute). This value indicates how much serum iron is bound to the transporter molecule.

What causes high TS?

High serum iron

High levels of transferrin saturation typically result from high levels of serum iron, which means that there is a high percentage of available transport spots filled with iron. It’s easy to visualize this as seat on a bus. The bus functions best when it is only about 20-50% full. Above 50% can indicate iron overload, which, similar to serum iron, can be due to just one meal or supplement.

What causes low TS?

Low serum iron

TS of less than 20% indicates low iron and possibly the risk of anemia. In an attempt to increase iron transport to cells, the liver produces more transferrin. But with low amounts of serum iron, we’ll find a low TS—a greater percentage of empty seats on the bus. Just like low levels of serum iron, low levels of TS can also be due to high inflammation.

Iron supplements

Total iron binding capacity

Total iron-binding capacity, or TIBC, is an indirect measurement of transferrin. In fact, it’s an inverse measurement–TIBC will be high when transferrin saturation (%) is low. High levels of TIBC indicate a low amount of iron “filling seats” on the bus. This is one way to tell if ferritin levels are elevated due to inflammation—a normal or high ferritin level coupled with high TIBC indicates inadequate intake of iron.

 

Red blood cells

Red blood cells (RBC) are responsible for transporting oxygen and other nutrients to tissues and carbon dioxide and other waste produces away from them.

What causes high RBC?

  • PolycythemiaHigh red blood cells are linked to elevated hemoglobin and hematocrit in a condition called polycythemia. It may result from due to high altitude, decreased oxygen concentrations in the blood, or genetic factors. Relative polycythemia can be caused from reduced blood volume, or dehydration.  

What causes low RBC?

  • Nutrient deficiency—Their production requires adequate intake of nutrients, particularly vitamin B12, folate and iron.
  • Disease—Like that of bone marrow, where RBC are produced, kidney or liver dysfunction, or diseases that cause hemolysis. Low red blood cells are generally indicative of a large condition.

 

Hematocrit

Hematocrit measures the portion of the blood that contains red blood cells. When blood is processed, red blood cells are separated from the plasma, the main fluid component of blood. Hematocrit measures the amount of blood that is made up of red blood cells. Hematocrit, hemoglobin, and red blood cells are typically all normal, high, or low together, since they are all dependent on the amount of red blood cells present.

 

Red blood cell distribution width (RDW)

Red blood cell distribution width is a measure of how much variation there is in the size of red blood cells. Under normal conditions, red blood cells should be uniformly produced with very little deviation in the width of each cell. If RDW is high, it means there is a high variation in red blood cell size. This can be caused by a nutrient deficiency that results in immature red blood cells being released at different stages in the maturation process.

 

Mean corpuscular volume (MCV)

Mean corpuscular volume measures the average volume of red blood cells. Smaller red blood cells (low MCV) are microcytic. This can result from inadequate iron intake or excess bleeding.

Larger red blood cells (high MCV) are macrocytic. This is typically caused by the release of immature red blood cells due to a folate or vitamin B12 deficiency. Correcting the deficiency will decrease MCV.

 

Mean corpuscular hemoglobin (MCH)

Mean corpuscular hemoglobin (MCH) is the average amount of hemoglobin found in RBC. The amount of hemoglobin per red blood cell depends on the amount of hemoglobin produced and the size of the red blood cell. During iron deficiency, there is less hemoglobin produced and smaller red blood cells are produced. A low MCH can indicate iron deficiency anemia or microcytic anemia.

MCH levels can be high due to macrocytic anemia, when very large red blood cells are produced as a result of inadequate vitamin B12 or folate. These large red blood cells can carry more hemoglobin.

 

Mean corpuscular hemoglobin concentration (MCHC)

MCHC results are similar to MCH, but measures hemoglobin as an average concentration within a single red blood cell. Low levels typically indicate microcytic or iron deficiency anemia. High MCHC can result from an increased need for hemoglobin or oxygen. This primarily is seen in smokers.

 

People most at risk for iron deficiency

Premenopausal females

Some individuals are at an increased risk of iron deficiency, primarily premenopausal females, as monthly menstruation results in blood loss. The body is typically a shrewd recycler of iron, but with blood loss, that possibility is off the table. Compared to males, premenopausal females require more than twice the amount of iron (18mg vs. 8mg, respectively). After menopause, women require 8mg, too. Pregnancy also drastically increases iron needs to 28mg per day since blood—and a new person—is being created rapidly.

Vegans and vegetarians

As you may imagine, vegans and vegetarians that do not consume red meat at all are at a greater risk of iron deficiency. Red meat is not the only source of iron in the diet, but it is the most significant, readily available, and readily consumed source in the US.

Endurance athletes

Another factor that can further increase iron needs is endurance activity. Heel strike (when the foot hits the road during activities like running) causes red blood cells that are flowing through capillaries in the bottom of the foot to rupture, leading to increased iron loss.

Iron Absorption

How to get enough dietary iron

Somewhat surprisingly, the best sources of iron are mollusks like clams, mussels, and oysters. They also happen to be some of the best sources of the other trace minerals as well. Octopus and whelk are also very high in iron. Red meats are also high in iron, but white meats like chicken and turkey are not.

Vegetarian sources also contain iron, but unfortunately it is in a form that is more difficult for the body to absorb. The iron in these foods is also accompanied by natural compounds that inhibit the absorption of iron by binding to it and then transporting it out of the body. These compounds are phytic acid, which is found in the highest amounts in grains and legumes, and oxalic acid, which is found in high amounts in a range of plant foods, including spinach and almonds.

Plant-based eaters often site spinach and beans at the best sources of iron, but the body can realistically only absorb a very small amount of the iron in these foods due to the phytic acid and oxalic acid. Plant-based sources of iron also have decreased bioavailability due to its oxidized form—Fe3+ is found in plants and must be reduced to Fe2+, the form in animals, in the small intestines before it can be absorbed.

To find out the status of your iron group and the best foods to improve your iron based on your preferences, it’s best to get a comprehensive blood test every few months.

 


References:

[1] Weatherall D, Akinyanju O, Fucharoen S, et al. Inherited Disorders of Hemoglobin. In: Jamison DT, Breman JG, Measham AR, et al., editors. Disease Control Priorities in Developing Countries. 2nd edition. Washington (DC): The International Bank for Reconstruction and Development / The World Bank; 2006. Chapter 34.Available from: https://www.ncbi.nlm.nih.gov/books/NBK11727/Co-published by Oxford University Press, New York