Anemia (including iron deficiency)

• blood volume - The circulating volume of red blood cells and serum. The blood volume of the average adult is about 10 pints (or 5 liters).
• serum (plasma) - The liquid portion of the total blood volume. Serum is composed of water, electrolytes, albumin, and other proteins (such as antibodies).
• hemoglobin - The molecule in red blood cells that binds oxygen. In the lungs, where oxygen concentrations are high, hemoglobin will bind oxygen. When the blood cells enter a low oxygen environment (in the capillaries -- particularly in muscle fibers involved in exercise), hemoglobin releases bound oxygen. Iron is one of several critical components for hemoglobin production (if the total body iron levels are low, the hemoglobin levels will be low)
• red blood cells (rbc) - The cells which contain the hemoglobin molecule.
• whole blood - Red blood cells and serum. 10 pints in the average adult.
• hematocrit (hct) - An expression of the percent of whole blood that is just red blood cells. In a normal adult the hematocrit is 40 to 45% of the total blood volume, thus a normal hematocrit is 40 - 45%.
• hemoglobin concentration (hgb) - The actual amount (weight) of hemoglobin (in gms) present in 100 grams of whole blood. It is just another way to think of the oxygen carrying capacity of a certain volume (pint, cc, etc.) of blood. It is often used as an alternative to the hct. to quantify the oxygen carry capacity of whole blood. A normal hemoglobin is 14 to 15 grams percent (14 to 15 grams of hemoglobin per 100 grams of whole blood).
• ferritin - The iron transport protein in the serum that supplies iron for red blood cell production. In anemias resulting from low total body iron stores (thus one of the raw materials for blood production is in short supply), the ferritin will be low.

ACQUIRED ANEMIA IN THE ATHLETE

• Dilutional or pseudoanemia (sports anemia)
• Exertional hemolysis
• Iron deficiency anemia

A) Dilutional Anemia

It is speculated that with work outs you become slightly dehydrated (which means your total blood volume decreases below normal - now 9.5 pints instead of the "normal" 10), the body senses this deficiency in the kidney (where the renin/angiotensin system kicks in) and in the pituitary (which increases ADH hormone release). Both of these lead to fluid retention (overcompensation) when you are able to drink adequately again.

The degree of dilutional anemia correlates with the intensity of exercise and is in the range of 5 - 20% below your hgb concentration (not a 20% drop in your absolute hgb or hct.) With moderate exercise, the hgb may decrease 0.5 gms, and in elite athletes the hgb may be as much as 1 gram lower than the athlete's "normal" range. Dilutional anemia may be seen within a few days of starting or intensifying exercise, and will correct back to normal within a few weeks of stopping exercise. It is high on the list of potential reasons for anemia when the ferritin is normal in the face of newly noted anemia, and can be confirmed if the hct or hgb returns to normal when the athlete stops exercising for one to two weeks.

Teleologically, are there potential benefits of a dilutional anemia? In the short term (before the body can produce additional red blood cells in response to the demands of exercise) it is a rapid way for the body to increase the blood volume and thus the cardiac stroke volume resulting in more blood being pumped through the lungs and muscle circulation per beat. It also decreases blood viscosity, which may be important to blood flow at the capillary level during exercise.

b) Exertional Hemolysis

• impact (mechanical trauma)
• turbulence in the blood vessels
• acidosis in the working muscle
• elevated temperature in the working muscle

• the size of the red blood cells in circulation is increased (the Mean Corpuscular Volume or MCV measures the amount of hemoglobin per rbc and is increased as young or new RBCs are bigger in size than older RBCs)
• the reticulocyte count is elevated (reticulocytes are the new RBCs formed in the prior few days and have a unique morphology on microscopic exam of the blood)
• the haptoglobin level is decreased (haptoglobin is a serum protein that scavenges hemoglobin released from ruptured blood cells) as it combines with the free hemoglobin released from the destroyed rbcs into the serum.

• eliminate other causes of hemolytic (broken blood cell) anemias such as medications, sickle cell trait, and other inherited fragile rbc syndromes.
• mitigate impact issues with soft shoes, orthotics, and by running on soft surfaces
• slow incremental increases in training (which seem to help)

But just adding an iron supplement to eliminate that possibility has risks as too much iron is toxic to normal liver, heart, and pancreas cells.

Dietary iron, from plant and animal protein, replaces the 1 to 4 mg daily iron lost through the kidneys and intestinal tract (via shedding colon lining cells). A person who stops taking in any iron at all (poor diet or absorption problems) has enough iron stores to support enzyme and red blood cell production requirements for about one year. So any imbalance, for example a new fad diet or low level blood loss, would take many months to reach the point where iron deficiency would impact performance.

Iron is one of the most difficult minerals to absorb from our diet. The efficiency of iron absorption varies between individuals as well as being dependent on the food source. We absorb 15% to 35% of the iron in animal protein versus 2% to 20% of the iron in vegetables and grains.

The recommended daily allowance for iron in an adult male is 8 mg per day and 18 mg/day for menstruating non-pregnant females.

Iron deficiency is more common in athletes than in non athletes. And is the most common true (versus dilutional - see above) anemia in athletes. It is most often the result of poor oral intake with the additional iron loss burden of menstrual blood loss in women. It is even more likely in elite athletes who commonly adopt unusual diets as they work to maintain competition weight. For those interested, this is an easy to understand summary with additional details.

Although there has been speculation on increased loss from the intestinal tract, this appears to be a greater risk in the runner than cyclist. Here are two links for more detail A and B. Red blood cells are smaller than normal (microcytosis) suggest an iron deficiency diagnosis. When there is not enough iron, new blood cells, lacking adequate hemoglobin, are smaller than normal. The next step is additional blood work. Blood test are indirect measures of body iron stores. If there is still a question, a bone marrow exam, which directly quantifies iron stores in the bone marrow, is the gold standard. Let's review the iron physiology again.

Iron absorbed from the intestine (this step can be bypassed with IV iron) binds to the protein transferrin which then transports iron to cells where it is used directly in cell repair or to the bone marrow where it is stored as ferritin.

The earliest change in a developing iron deficiency is a decrease in ferritin levels. Next the amount of transferrin that contains iron (expressed as a percent) increases. And finally the lack of iron begins to affect the production of hemoglobin and the blood count starts to fall (anemia). This in turn impacts the ability of the cells to carry oxygen to exercising muscle cells.

This article summarizes blood test options with examples of results in iron deficiency. If there are conflicting results, the blood iron level and transferrin are not as useful as the ferritin levels - so if they give conflicting result, the ferritin is generally considered the better of the two. But even for ferritin levels, blood levels can occasionally be misleading. Plasma ferritin is what is called an “acute phase reactant” which means levels may be elevated following vigorous physical activity or in an individual with an inflammatory illness. Thus, determination of ferritin levels should be postponed in athlete who have recently completed an acute bout of exercise training or in those with acute febrile illness). (underlining is mine). So to be accurate, a serum ferritin should be checked after a few days of rest (or at best only on days with mild activity. For those interested in more discussion of iron tests, this website is a nice resource.

The bigger challenge is deciding if a fatigued athlete who is not anemic might be in the early stages of iron deficiency and might benefit from iron supplements. The challenges of using a blood test to decide are:

1. "Normal" ranges are fuzzy, especially at the lower limits. Many people considered as normal for the purposes of establishing these normal range may actually be mildly iron deficient.
2. Transferrin and ferritin levels may vary with mild infections or other inflammatory processes.
3. As cellular energy enzymes may be more sensitive to low iron than hemoglobin production, fatigue can be a symptom of iron deficiency even with a normal blood count.

The recommended daily iron intake for an adult male is ~ 8 mg/day, and for a menstruating, non-pregnant females ~ 18 mg to replace iron losses from menstruation. The bio-availability of dietary iron is greatest for red meats (15% to 35%) compared to 2% to 20% for the iron in vegetables and grains. That is why vegetarians are at increased risk of becoming iron deficient.

If an athlete (especially vegetarians and women) is worried about becoming iron deficient, options for prevention include:

• for non vegetarians, increasing the intake of meat is an easy option
• the other is taking a multivitamin vitamin with no more than 15 mg of iron. A daily dose of 15 mg of iron is low risk. However, with a regular diet it is generally unnecessary. If you decide on a multivitamin, it should be separated from calcium supplements, fiber supplements, and caffeine, all of which can impair absorption.

For confirmed iron deficiency:

• ferrous sulfate 325 mg one to three times a day is the usual recommendation. Start slowly with one tablet per day as some athletes develop indigestion or bowel problems (both constipation and diarrhea) on iron supplements, symptoms which are dose related.
• recheck a blood count after two to four weeks of oral to assure the iron is being absorbed and doing its job. The blood count should be rising by then. If not, some people are poor absorbers and may need intravenous iron replacement.
• it will take two to three months to replete your body iron stores. Then it is time to switch to a prevention program. Do not continue the large treatment doses as the risk of iron overload disease is significant.

All studies to date fail to show a benefit from iron supplements UNLESS the iron deficiency is associated with anemia (references - 1, 2, 3). The most recent meta analysis of multiple studies confirms the lack of benefit in the absence of anemia. This has led to the conservative recommendation to treat only when anemic, especially with the significant risks of over treatment. Not only is there that risk of organ damage, animal models have shown that too much iron also decreases exercise performance.

My take aways:

• Mild iron deficiency can impact athletic performance before anemia develops.
• The risk for iron deficiency is greater in women and vegetarians.
• If you think you might be iron deficient, get a blood test before blindly adding a diet supplement. There are no studies supporting the idea that iron supplements without proven iron deficiency improves performance and iron overload can lead to irreversible health problems as well as impair performance.
• Consider a trial of iron if your ferritin is less than 35 micrograms/liter even with normal transferrin and hemoglobin numbers.

DONATING BLOOD

You won't notice much of a change in performance on moderate rides. However if you did intervals, you would notice a decrease in performance until the hemoglobin is replaced. It is a good idea to give blood on a rest day and keep the next few workouts light. And be sure to wait at least 2 weeks before entering a performance event. Over time, repeated blood donation might lead to iron deficiency. Use the prevention measures mentioned above to decrease your risk.

QUESTIONS

A.

• If your ferritin and % iron saturation are low, you need iron. So getting the blood tests are step 1.
• If you have normal iron levels, the chemo may be depressing red blood cell production and you may benefit from epo. As long as your hct is less than 50% you may be able to do sanctioned races while on it, but ask. You are in special circumstances with the chemo and might need a waver.
• If the blood test show that you are iron deficient, I'd suggest you use the supplements. It will take too long to get levels up to normal with red meat alone, and you want to feel back to you normal more quickly than that. Once your iron levels are back to normal, you should be able to maintain with diet (even meat free) alone. But an occasional supplement every other day would provide a little insurance from the effects of an unbalanced diet.

Q. I was recently queried by a reader about their laboratory results and the possible need for iron supplements. Values of interest (and I'll leave off units of measurement):

• serum iron 103 (normal > 109)
• serum transferrin 234 (normal >109)
• serum ferritin 92 (normal >67)
• hct (blood count) 45 (normal 47)

A. In answering this question I am going to use direct quotes from a very nice summary article I recently ran across.

1. Why should an athlete care about iron deficiency? Because low body iron stores will impact performance.

The oxygen carrying capability of blood is directly related to the hemoglobin molecule concentration which is in turn is directly related to iron availability (a key component of hemoglobin production). And there is a speculative component that iron deficiency may impact muscle enzyme levels directly (iron is part of many enzyme systems). In addition "...impairment of exercise capacity in anemic individuals may reflect more than reduced oxygen transport. Subjects with low hemoglobin concentrations also manifest a decrease in blood viscosity and reduction in systemic vascular resistance, effects that increase cardiac work and strain circulatory function."

2. Is this athlete anemic? Questionable

Although suggestive, these numbers (hct 47) do not support a clear diagnosis of anemia. Blood counts do vary a few points from blood draw to blood draw, so a hct of 45 on repeat might be 47. And individuals have their own "normal" that may always be a bit lower or higher than the population averages. In addition, to quote "......Borderline low hemoglobin concentrations with normal ferritin concentrations are sometimes observed in athletes...."

3. Does this athlete have iron deficiency (early, without anemia)?

This is where it gets murky. Blood test are indirect measures of body iron stores. The gold standard is a bone marrow exam that directly assesses body iron levels (iron is stored in the bone marrow). The blood iron level and transferrin are not as useful as the ferritin levels, so if they give conflicting result, the ferritin is generally considered the better test for diagnosis of body iron levels.

"Serum iron levels demonstrate a great deal of variability over time (both circadian and rate of release from the reticuloendothelial system), bear no reliable relationship to ferritin concentration, and cannot be expected to accurately reflect body iron status."

"Ferritin circulating in the blood stream accurately reflects body iron stores and serving as a reliable marker of iron deficiency. A value of 1 ng/mL of ferritin corresponds to about 5 to 9 mg of stored iron."

But a qualifier here - "...It is important to recognize that plasma ferritin is an acute phase reactant, and levels will be consequently elevated following vigorous physical activity or in an individual with an inflammatory illness. Thus, determination of ferritin levels should be postponed in athletes in an inflammatory state (i.e., those who have recently completed an acute bout of exercise training or in those with acute febrile illness)." This means that one could be iron deficient with a low serum ferritin and yet see it falsely elevated into the normal range after a bout of strenuous activity.

So to increase its predictive value, a serum ferritin should be checked after a few days of rest (or at best only mild or rest day activity.

The answer to the original question? It is unclear with the information available.

• The blood count is not diagnostic of iron deficiency (anemia would help to confirm suspected iron deficiency based on borderline blood iron levels, if present).
• The serum iron is not a reliable indicator of iron deficiency.
• The serum ferritin says "normal body iron stores" but if it was done a day after vigorous activity it might be falsely elevated into the normal range.

Should they just take iron "just in case"? There are definite risks to this approach as iron can be toxic to the liver, heart, and pancreas if taken at high doses for long periods of time. Again, to quote: "Expert opinion is in agreement that, considering these possible risks, athletes with normal ferritin levels should not take iron supplements."

The article: "Supplement Worth Re-considering"

"Last week's piece about the potential benefit of iron supplements ("A Supplement Worth Considering") sparked lots of feedback, including e-mails from six medical professionals. In general, the docs expressed great concern about men taking extra iron. Although we included a warning about that and the wisdom of consulting a physician first, they either overlooked the caveat or wanted to emphasize it. Important comments from four doctors are below."

• Gabe Mirkin, M.D. "It is extraordinarily dangerous for a healthy man to take extra iron unless he suffers a deficiency. While women lose iron regularly through menstruation, men lose iron only through bleeding. No man should ever take iron unless his blood test, called ferritin, shows that he is low on iron. Excess iron can deposit in the liver to cause cirrhosis, pancreas to cause diabetes, and the heart to cause a heart attack. Iron is an oxidant that damages tissue. High levels increase risk for heart attacks."
• Lisa Weissmann, M.D. "I am a hematologist (physician specializing in blood disorders) as well as an avid road bike rider. The gentleman in the story had developed iron deficiency anemia from donating blood over a long period of time. For him, the cause of his anemia was iron deficiency, and therefore iron in his case was essential to restore him back to normal. However, anemia can be from a multitude of causes, and iron will not help unless it happens to be iron deficiency. Moreover, iron, by itself, in people who are not iron deficient or anemic, will have no benefit in terms of performance."
• Paul Pagoff, M.D. "Iron deficiency [in men] almost never occurs because of diet deficiency. In men with real iron deficiency the cause is likely blood loss of some sort, including blood donation. If there is no clear explanation then cancer in the intestinal tract needs to be ruled out."
• Steve Weeks, DDS. "Iron is needed for hemoglobin production, as indicated in the article. However, iron is highly conserved in normal males, and dietary requirements for replacement are quite small. Men who have low iron levels as reflected by low hemoglobin or hematocrit should not simply take iron supplements, but should receive medical evaluation for the cause of the deficiency. Some possibilities are gastric ulcer, colon cancer or other form of gastrointestinal bleeding. Less commonly, it is decreased production of red blood cells in the bone marrow owing to the influence of drugs or disease. You did say, correctly, that people starting on supplements should consult their physician. However, it might bear repeating that iron deficiency, especially in men, could be serious and that, as tempting as it is to pop over to the drug store for iron pills, a physician should be involved."

The bottom line, perhaps, was provided by this e-mail from a roadie who asked that his name not be used: I am not an expert on this but do have an experience regarding the blood issue. My cardiologist, also a bike racer, found out that I donated blood regularly. His immediate response was that sport cyclists should not donate blood without a serious review of the pros and cons. "Riders may be better off reducing their blood donations than taking iron supplements."