Iron Status & Fatigue in the Endurance Athlete Should I get a serum ferritin?

Iron Status & Fatiguein theEndurance AthleteShould 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 Fe++

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

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,

It is unlikely that skeletal muscle iron-dependent compounds are related to fatigability during exercise

therefore...

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

Examine effect of Fe++ supplements and training on virtual time-trial performance

Examine effect of Fe++ 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.

Chicharro, et al. Br J Sports Med. 2004; 38:418-421.

Athletes: 50 pro cyclists + 15 “Olympic class endurance runners”(vs only cyclists in Deugnier et al. MSSE. 2002; 34:876-880.)

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 non-anemic, 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 CNS-mediated 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)