Iron Status & Fatigue
in the
Endurance Athlete
Should I get a serum ferritin?
Example Case
RJ Dimeff. Clin J Sports Med 2000
Female college middle-distance runner
CC: Fatigue, abdominal cramping
History, exam, labs unremarkable...
Low Ferritin with a “normal” Hb/Hct
Rx: Ferrous sulfate, iron-rich foods
Slowly gets better
Same song, second verse the following year
Rowland, et al.(1989)
This study was very poorly done...
• but was a catalyst for the concept of using
• supplements in endurance athletes
Convenience sample of girl H.S. runners
Pre-season & post-season
Traditional max tests (ramp protocol)
Time to volitional exhaustion
No control of training programs
++
Fe
Fatigue Work-Up
History (>90% in athletes)
Exercise/Rest Provocative or Palliative?
Anxiety & Depression
Meds/Substance Abuse
Exam (<5%)
Infection/Inflammatory/Metabolic
Cardiopulmonary/Neuromuscular
Malignancy (PM/DM)
JL Beard. J. Nutr. 131: 568S–580S, 2001.
Fatigue Work-Up
Labs (5-10%)
CBC
UA
Complete Metabolic Profile
TSH
Consider ECG / CXR / OGTT
Rheum screen
ESR, CK, Rheumatoid Factor, ANA
Overtraining...or maybe
Iron?
Definition of fatigue vs endurance
Quantifying fatigue in the physiology lab
Studies of iron supplementation & fatigue
Iron metabolism
Fear & loathing (hemochromatosis)
A (not so) final analysis
What is Fatigue?
Christensen, E.H. 1960. Muscular work and fatigue, in
Muscle as a Tissue, eds. K.Rodahl, S.M.Horvath, New
York, McGraw-Hill.
Physical fatigue: a state of disturbed homeostasis
attributable to work and to work environment.
What is Endurance?
Åstrand, P.-O., Rodahl, K., Dahl, H.A., Strømme, S.B.
2003. Textbook of Work Physiology, 4th edition.
Champaign, IL.
No definition of endurance
Physical endurance - GEM definition:
A state of prolonged homeostasis despite elevated levels
of external physical work; resistance to physical fatigue.
What is Fatigue?
Characterization of exertional fatigue:
Muscle fatigue = 1/endurance
In situ / In vitro preparations
Multiple parameters needed to quantify
Highly sensitive to independent parameters
N.B.: SERCA the likely final common pathway
What is Fatigue?
Loss of muscle contractility & lusitropy
Highly sensitive to independent parameters:
Tpass
Stimulation frequency (twitch vs tetanic)
O2 supply (ml O2 / min, not just Hb/Hct)
Other (e.g., sympathetic stimulation, pressors)
JL Beard. J. Nutr. 131: 568S–580S, 2001.
JL Beard. J. Nutr. 131: 568S–580S, 2001.
Again, Fatigue is...
Loss of contractility and lusitropy
Highly sensitive to O2 supply
TCA cycle and Ox Phos pathways are not rate-limiting in
the O2 transport chain and are in excess capacity,
therefore...
It is unlikely that skeletal muscle iron-dependent
compounds are related to fatigability during exercise
OK...What About Humans?
Problem: no good objective measure of “muscle failure”
Volitional exhaustion
Relative intensity a critical factor
Max steady-state (i.e., Vt, [La]4 mM, etc.)
Poor control of non-oxidative energy contribution
Failure of contractility
Rhythmic isometric/isokinetic contractions
Low %MVC, low duty cycle
1 contraction / 5 sec, electrical stimulation, etc.
Fatigue in Humans?
Longitudinal studies are very problematic
Constant O2 supply?
Increase in Hb increases O2 delivery
Constant fitness?
Constant absolute vs relative intensity?
Constant non-oxidative contribution?
Existing studies do two interventions
Training
Iron supplementation
Haas, et al.
Examine effect of Fe++ supplements on running economy
++
Fe
Examine effect of
supplements and training on
virtual time-trial performance
++
Fe
Examine effect of
supplements on isokinetic
contractility of knee extensors (not electrically stimulated)
Examine effect of Fe++ supplements on ventilatory
threshold in trained subjects
Haas group. Am J Clin Nutr. 1997. 66:334-341.
Hinton et al., (Haas group). JAP. 2000. 88:1103-1111.
Hinton et al., (Haas group). JAP. 2000. 88:1103-1111.
Hinton et al., (Haas group). JAP. 2000. 88:1103-1111.
Brutsaert et al. (Haas group). Am J Clin Nutr. 2003. 77:441-448.
Brutsaert et al. (Haas group). Am J Clin Nutr. 2003. 77:441-448.
Brutsaert et al. (Haas group). Am J Clin Nutr. 2003. 77:441-448.
Hinton & Sinclair. Eur J Clin Nutr. 2007. 61:30-39.
Iron / Fatigue Research
Difficult studies, but fatally-flawed designs
Hb increases with
++
Fe
supplements
Little/no control of relative intensity
Various inequalities between groups
Multiple interventions (exercise and Fe++)
Volitional fatigue
Vt effect? - possibly but Vt ≠ fatigue
Iron Metabolism
Could sub-normal iron metabolism contribute to fatigue
via non-O2 transport mechanisms?
What does ferritin do, anyway?!
JL Beard. J Nutr 2001; 131: 568S–580S.
JL Beard. J Nutr. 2001; 131: 568S–580S.
Ponka, et al. Semin Hematol. 1998; 35:35-54.
EC Thiel. J Nutr. 2003; 133:1549S-1553S.
Ryter & Tyrrell. Free Rad Bio Med. 2000; 28:289-309.
Ponka, et al. Semin Hematol. 1998; 35:35-54.
Ryter & Tyrrell. Free Rad Bio Med. 2000; 28:289-309.
Smith & Roberts. Clin Chem. 1994. 27:335-440.
Forget About Ferritin?
• Well,...no. It can be dangerous.
Hemochromatosis genotypes (HFE mutations) are highly
prevalent in the population - one of the most common
congenital mutations.
There continue to be no case-reports of a runner with
phenotypic hemochromatosis.
Never is a long time.
Athletes: 50 pro cyclists + 15 “Olympic class endurance runners”
(vs only cyclists in Deugnier et al. MSSE. 2002; 34:876-880.)
Chicharro, et al. Br J Sports Med. 2004; 38:418-421.
Forget About Ferritin?
Ferritin gene knockout - lethal in utero
Population prevalence of HFE - 33%
Athlete prevalence of HFE - 50%
•
Could the hemochromatosis gene be protective against
iron-deficiency in runners?
Non-O2 Transport
++
Fe ?
CNS structures that contain Fe++
Cortex, striatum, cerebellum, thalamus
Fe++ a co-factor in myelination
Dopaminergic regions “affected” ≥15% low
Mesolimbic & striatonigral tracts
Motor control, perception, motivation
Serotonin/Norepinephrine - not affected
A (Not So) Final Analysis
James Beard on iron deficiency:
•
“Thus, although it is convenient at times to categorize
individuals as iron-deficient anemic vs iron-deficient nonanemic, this is not a biological reality”.
A (Not So) Final Analysis
Ian Shrier on iron deficiency:
•
“Low ferritin with hemoglobin in the mid- to upper normal
range is at best a relative indication for iron
supplementation: low ferritin with hemoglobin in the low
normal range is a stronger, yet still relative, indication for
iron supplementation in athletes”.
A (Not So) Final Analysis
Ferritin still could be related to fatigue through CNSmediated pathways
Motor control
Motivation
Thermoregulation
Other?
Should Runners Take Iron?
All things being equal, if your competitor has a higher
arterial O2 content than you, your only hope is that they
will have a bad day...
Competitive distance runners should probably take an iron
supplement and/or eat iron-containing foods, i.e., red meats,
unless not winning doesn’t bother them
Menstruating Women - very low risk of hemochromatosis
Men - also at low risk?
Someday...check a ferritin. If it’s not high, forget about it
• (at least while they’re a competitive runner)