07 July 2014

Iron deficiency, anemia and supplementation in ultramarathon running

The summer training is progressing well and I have this week returned to spending more time in the local ski slope to get more long-distance vertical meters in my legs. I have been slightly bothered by my torn left knee – only a superficial skin wound, but rather large and as it also got somewhat infected it will certainly leave an impressive scar. There are now exactly 49 days (7 weeks) until the start of Petite Trotte à Léon (PTL) and I have reached the stage in the training where it feels like I would be able to do it reasonably well if the race would occur within the next few days. Now it is more a matter of sustaining rather than improving my form. Still, I will have some more weeks of really hard training before going on a short vacation which also will be the start of more technical speed and aerobic training.

I have also started to prepare by increasing my iron stores through both food and supplementation. I have, probably for genetic reasons, always had a borderline hemoglobin value of around 14 g/dL (140 g/L) and my iron deposits have also been rather low with borderline serum ferritin values. Not that I have a clinically significant iron depletion/deficiency (sideropenia), but when I have started to run longer races at high altitudes I think it important to have as optimal values as possible. Normally, I am not using any supplementation, but before TDG last year and now before PTL I will try to optimize my oxygen transporting system not only by training to increase my VO2max, but also by iron supplementation.

I would not use iron supplementation if I had better hemoglobin and iron values. I was therefore quite surprised to see in study of 489 100-mile mountain ultramarathon trail runners that over 75% use vitamin and mineral supplementations (Hoffman & Fogard “Demographic characteristics of 161-km ultramarathon runners” Res Sports Med 2012; 20: 59-69). I think that this not only is unnecessary, but perhaps even damaging – I just read an article describing the results of a double-blind randomized controlled trial of 54 healty volunteers receiving either vitamin C (1000 mg) and vitamin E (235 mg) or placebo daily for 11 weeks while undergoing an endurance training program (Paulsen et al “Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial” J Physiol 2014; 592: 1887-901). In this study vitamin C and E supplementation hampered cellular adaptations in the exercised muscles, and although this did not translate to less improvement in VO2max and endurance testing, the authors advocate caution when considering antioxidant supplementation combined with endurance exercise. On the other hand there are indications that vitamin C supplementation is beneficial for prevention of upper respiratory tract infections (colds) and exercise-associated bronchoconstriction in association with long endurance races (Hemilä & Chalker “Vitamin C for preventing and treating the common cold” Cochrane Database Syst Rev 2013; 1: CD000980; Hemilä “Vitamin C may alleviate exercise-induced bronchoconstriction: a meta-analysis” BMJ Open 2013; 3: pii: e002416).

While there clearly are some doubts whether supplementation of vitamin C is beneficial or damaging there are more and more data indicating that iron supplementation is benefical in athletes with low iron deposits and iron deficiency anemia. A recent PhD graduate thesis by Dr Sandström from Gothenburg University showed that the prevalence of iron deficiency in young female athletes, for instance the Swedish female national soccer team, was over 50%, despite better diet and less loss by menses than a control group (and also controlling for other risk factors such as Helicobacter pylori infection and vegetarian diet) (thesis available online at https://gupea.ub.gu.se/handle/2077/35460 ). He found higher values of the inflammatory protein serum hepcidin in the athlete group compared with the non-athletes and, as hepcidin downregulates the protein ferroportin important for dietary iron absorption this could be a mechanism beind so called “sports related iron deficiency”. There have been a number of studies in recent years showing up-regulation of hepcidin in response to endurance training in general and running in particular (see for instance Kong et al “Hepcidin and sports anemia” Cell & Bioscience 2014; 4: 19; Peeling et al “Iron Status and the Acute Post-Exercise Hepcidin Response in Athletes” PLoS ONE 2014; 9: e93002; Auersperger et al “Exercise-Induced Changes in Iron Status and Hepcidin Response in Female Runners” PLoS ONE 2013; 8: e58090). However, these findings are still from small early studies and further data is needed to certainly show that this is the mechanism behind sports anemia and it is probably not relevant for all athletes as, for instance, one study of six males running a 100-km ultramarathon failed to show any changes in hepcidin values (Kasprowicz et al “Running a 100-km ultra-marathon induces an inflammatory response but does not raise the level of the plasma iron-regulatory protein hepcidin” J Sports Med Phys Fitness 2013; 53: 533-7).

The relation between exercise and hepcidin (From Sandström's thesis)
Ultramarathon runners are probably at higher risk of iron deficiency than other endurance athletes for several reasons. Firstly, the inflammatory reaction/acute phase reaction in response to injury in ultramarathon running has consistently been shown to be very high and this would probably lead to high hepcidin values (see articles refered to above). Secondly, while most hematologic paramaters appear normal after ultramarathon training and racing, there appear to be changes indicating induction of some kind of changes in the iron metabolism (see for instance Dickson et al “Effects of ultra-marathon training and racing on hematologic parameters and serum ferritin levels in well-trained athletes” Int J Sports Med 1982; 3: 111-117; Fallon et al “Changes in haematological parameters and iron metabolism associated with a 1600 kilometre ultramarathon” Br J Sports Med 1999; 33:27-32; Fallon & Bishop “Changes in erythropoiesis associated by reticulocyte paramaters during ultralong distance running” Clin J Sports Med 2002; 12: 172-178; Banfi et al “Behavior of hematological parameters in athletes peforming marathons and ultramarathons in altitude (‘skyrunners’)” Clin Lab Haematol 2004; 26: 373-377). In contrast, contrary to common belief, the effects of foot-strike haemolysis on red-blood cell count and haemoglobin values appear to be negligible after ultramarathon running (Lippi et al “Foot-strike haemolysis after a 60-km ultramarathon” Blood Transfus 2012; 10:377-83). Furthermore, even though ultramarathon running clearly induces gastrointestinal bleeding that might be associated with nausea, diarrhea, abdominal cramping and bloating, it appears neither to influence RBC count or haemoglobin values (Baska et al “Gastrointestinal bleeding during an ultramarathon” Dig Dis Sci. 1999; 35: 276-9; Thalmann et al “Proton pump inhibition prevents gastrointestinal bleeding in ultramarathon runners: a randomised, double blinded, placebo controlled study” Br J Sports Med. 2006; 40: 359-62).

There are of course no good large randomized-controlled trials studying iron-supplementation in ultramarathon running, but in running there are some smaller studies indicating a positive effect in iron-deficient, non-anemic male and female runners (for instance Garvican et al “Intravenous iron supplementation in distance runners with low or suboptimal ferritin” Med Sci Sports Exerc 2014; 46: 376-85; Hinton & Sinclair “Iron supplementation maintains ventilator threshold and improves energetic efficiency in iron-deficient nonanemic athletes” Eur J Clin Nutr 2007; 61: 30-39). One reason that studies of iron supplementation in sports anemia historically has yielded small or diverging results might be due to the exercise-induced inflammatory reaction with high hepcidin leading to decreased gastrointestinal uptake of also supplemented iron. It is therefore probably important to time to iron supplementation so that it is not occurring at the peak of the inflammatory reaction and hepcidin rise after training.

In the end, I think no supplementation can replace a healthy diet and this time of the year it is easy to find good sources of healthy nutrients both in the food stores and close to the trail. I am particularly fond of blueberries, as I have written in a previous blog post. Even though the health effects of supplementation with polyphenols found in blueberries still needs to be investigated further (see for instance the recent study by Nieman et al “Influence of a polyphenol-enriched protein powder on exercise-induced inflammation and oxidative stress in athletes: a randomized trial using a metabolomics approach” PLoS One. 2013; 8:e72215), I love the taste and what better to eat after a long trail run than a piece of blueberry pie?
Blueberry pie


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