Are you iron deficient?

How are you feeling today? Tired? Is it your active lifestyle wearing you down? Or is it a sign of something more serious? Complaints about fatigue seem ubiquitous. Perhaps it’s a product of a culture with little downtime. Yet from a medical perspective, fatigue can’t be dismissed with a simple instruction to “get more sleep”. When approached in the pharmacy, I take the perspective that anyone actively seeking advice on treatment probably needs a medical assessment. That’s not something I can offer, but I try to impress upon patients the importance of finding the cause, rather than reaching for any quick fix that may be for sale. (Energy drink, anyone?) And I can use the opportunity to discuss the appropriate role of supplements for treating fatigue.

I’ve elaborated in other posts why I’m not a fan of routine vitamin or mineral supplementation in the absence of any established need – the risks with some supplements are concerning, and the benefits haven’t been clearly established. Recently I’ve had a my position on supplements questioned by people interested in taking iron supplements to treat fatigue. They’re correct, to a degree: fatigue and iron are usually linked. Iron deficiency is the most common nutritional deficiency in the world. And iron deficiency is the major cause of anemia. The statistics are remarkable – in developing countries, 50% of pregnant women and 40% of children are anemic, a result of iron deficiency as well as other illnesses. In contrast with other vitamin deficiencies, anemia is also present to a significant extent in developed countries: 19% of the population in the Americas and 10% in Europe. The incidence is highest in women, particularly pregnant, and youth.

So why not a trial of iron supplements? “Iron loss explains why you’re tired all the time,” suggested a recent Atlantic article. That statement was based on a recent paper that does suggest that iron supplements may reduce fatigue – even in those without anemia. But is supplementation warranted on this basis? In some cases, it could be the wrong approach. Fatigue is a non-specific symptom, so serious causes should be ruled out before thinking about a treatment plan. Medical or psychiatric issues can cause fatigue – depression among the most common. Medications are also a significant (and frequently overlooked) direct cause of fatigue. The long list include antihistamines, opioid narcotics, muscle relaxants, and some antidepressants. Chronic fatigue syndrome is a rare but disabling cause of fatigue that may also be a consideration.

A medical workup will usually include a physical examination and laboratory investigations to rule out specific causes like thyroid dysfunction, cancer, heart failure and other conditions. Laboratory tests will always include hemoglobin and ferritin, two measure to evaluate the iron stores in the blood. The body holds about 4 grams of iron. Two grams is within the hemoglobin of red blood cells, and most of the remainder is stored in ferritin. Low iron can be spotted here.

If there is a confirmation of anemia present, there’s further considerations. Anemia is usually due to increased iron losses, or decreased intake. Fixing the deficiency, without identifying the cause, is foolish. Iron loss can be a signal of diseases like cancer. Or it may be something more straightforward. Pregnancy and menstruation are common causes. Celiac disease is also possible. Reduced absorption is a less common cause of anemia, but several drugs can make matters worse.

When causes of loss have been investigated, treatment considerations are more straightforward. For most people, oral iron supplements are effective, inexpensive, and (generally) well tolerated. When iron supplements are necessary, here are a few considerations:

  • The degree to which the different types of supplements cause side effects seems to be directly related to the amount of elemental iron per pill. Slow release and other forms of iron are more expensive and may be better tolerated, but may also contain less iron.
  • Iron should be taken on a empty stomach to maximize absorption – but few people seem to tolerate this. It’s a trade off, and you need to determine what works. Better to find a dosing schedule that you’ll stick to, rather than making yourself miserable with supplements, or quitting prematurely.
  • For maximal tolerance and absorption, spread doses out throughout the day.
  • Vitamin C may help iron supplement absorption. Taking a tablet with each dose can be considered. Some prefer orange juice instead.
  • Liquid iron supplements are popular, but they’re an inconvenient and expensive way to replace iron stores. I usually suggest generic iron tablets to start, with liquids only where all other dosage forms have failed.
  • Your stools will turn black. Don’t be frightened. Iron isn’t fully absorbed.
  • To replace low iron levels, you should aim for 150-200 mg of elemental iron per day. 300mg per day is about the maximum that people can tolerate.

There is some data suggesting linkages between iron levels and cancer, and others that draw associations between high iron intake and cardiovascular disease. While the relationships are unclear, it suggests that supplementation in the absence of deficiency may not be risk free. Iron is toxic and even fatal at high doses. In children, excessive iron is much more toxic than many prescription drugs, and is a leading cause of poisoning death. (Ten adult-strength ferrous sulfate tablets can kill a small child.) With respect to daily supplementation in the absence of a deficiency, adults taking up to 45 mg of elemental iron per day is generally considered safe. Multivitamins for pregnant women will usually a small amount of iron, to offset pregnancy-related losses.

Iron stores can be depleted before any anemia is present. It’s traditionally thought the fatigue related to iron deficiency is due to anemia. That hypothesis was tested in a study published in the CMAJ earlier this year which randomized 198 premenopausal women complaining of fatigue, with low ferritin, but not anemia, to iron supplements or placebo. By Vaucher and associates, it’s entitled, Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. All other causes of anemia had to have been ruled out in order to participate. The two treatment groups were comparable with the notable exception that the “iron” group had more women with significantly lowered hemoglobin or ferritin. However, mean values were similar. Also notably the study was sponsored by the manufacturer of the iron supplement studied.

The treatment consisted of 80mg/day of elemental iron (packaged as a slow-release tablet combined with Vitamin C) for 12 weeks. Both groups improved with treatment, as evaluated by a validated scale that measures fatigue with a score of 0-40. Given fatigue can wax and wane, it’s possible that they entered the study at a more fatigued point, and simply improved with time. There was a modest improvement over placebo in the iron group: Women taking iron reported a net improvement of 3.5 points over placebo, which was barely statistically significant. And given the subtle differences between the groups, however, I’m not convinced it’s relevant. So while this is being heralded by purveyors as a 50% improvement, whether it’s a real and meaningful improvement is difficult to say. In a post-hoc analysis , the authors estimate a number needed to treat of 10, suggesting that 10 women reporting significant fatigue need to be treated for 12 weeks in order for one woman to experience less fatigue after 12 weeks. Not that impressive. In contrast to the subjective reports of fatigue, objective measures all improved as expected, including ferritin, hemoglobin, and other. Blinding seems to have been maintained – both groups had equal amounts of gastrointestinal discomfort. But given iron stains the stool black, it’s not clear why they didn’t ask participants to guess their allocation. And overall, the treatment was well tolerated. The bottom line from this study seems to be that iron supplements in the absence of anemia restore biochemical measures, but their effect on fatigue is modest.

One group that asks me about iron frequently are marathon runners – because I’m a runner too. Running has been associated with iron loss for decades, so I’m often questioned about supplements to prevent any possible anemia. The data suggests that iron deficiency in male runners is rare, so supplementation in the absence of a known deficiency is not advisable. For female athletes, deficiency and anemia is more common. Whether this justifies routine screening is unclear, but my advice to athletes and non-athletes who are concerned about iron is the same: Maximize the consumption of iron in the diet by ensuring a regular intake of iron-rich foods. Meat products provide “heme iron” which is well absorbed, and “non-heme-iron”, which is not. Plants only contain non-heme-iron. Vegetarians, particularly females, and especially vegetarian female athletes, must carefully monitor their diets to ensure they’re consuming enough iron.

Conclusion

Fatigue can be caused by an array of conditions. Iron deficiency is a common cause, though whether iron supplements offer benefit in the absence of anemia remains to be established. Children and women, particularly pregnant women, need adequate iron in their diet. While low-dose supplements are considered safe and may be helpful in meeting daily requirements, specific supplementation isn’t necessary or advisable in the absence of a clear deficiency. And just because it’s a supplement doesn’t mean it can’t be harmful. Iron supplements can be toxic in children, and should be stored like any other potential poison.

Reference
Vaucher, P., Druais, P.L., Waldvogel, S. & Favrat, B. (2012). Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial, Canadian Medical Association Journal, 184 (11) 1254. DOI: 10.1503/cmaj.110950

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