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🤔Why does iron deficiency cause fatigue, even in the absence of anemia?
I have often equated iron with hemoglobin and oxygen-carrying capacity.
But there is so much more to it!
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It has been observed since the 1800s that one can experience fatigue in the setting of iron deficiency, even with a normal hemoglobin value.
And administering iron mitigates these symptoms.
pubmed.ncbi.nlm.nih.gov/13800263/
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It wasn't until 1960 that we saw RCT evidence support.
That year, Beutler published a study in which women with hemoglobin >12g/dL were randomized to iron supplementation or placebo.
🔑Those receiving iron had a greater improvement in symptoms.
pubmed.ncbi.nlm.nih.gov/13800263/
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More recent data support the idea that the administration of iron to those who are deficient and not anemic decreases fatigue.
ncbi.nlm.nih.gov/pmc/articles/P…
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Additional evidence that iron deficiency alone can cause symptoms comes from studies of polycythemia vera, a condition associated with high rates of:
➤Iron deficiency AND
➤Fatigue
Despite high hemoglobin values!
twtr.to/sSqd
twtr.to/3tLE
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What explains these findings?
🔑In short: iron does a lot more than carry oxygen.
But, for this thread, it may be most interesting to concentrate on iron's role in mitochondrial function.
pubmed.ncbi.nlm.nih.gov/35011874/
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In 1976, Finch et al published a study on exercise in normal and iron-deficient rats.
In an ingenious move, the investigators removed anemia as a variable by keeping the hemoglobin stable via exchange transfusion.
jci.org/articles/view/…
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Iron-deficient rats showed worse running ability as compared to control animals.
This was corrected with iron therapy.
🔑And, levels of a mitochondrial iron-containing enzyme, α-glycerophosphate dehydrogenase, paralleled worsening and improvement.
jci.org/articles/view/…
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These findings help explain why iron is effective in the treatment of heart failure, even without anemia. In particular, one meta-analysis reported a...
➤31% reduction in heart failure hospitalizations
...with iron compared to placebo.
ncbi.nlm.nih.gov/pmc/articles/P…
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And just as with earlier rat studies, experiments demonstrate that those with heart failure and myocardial iron deficiency have:
🔑Reduced function of mitochondrial enzymes, particularly those required for the Krebs Cycle.
Yes, that KREBS CYCLE.
pubmed.ncbi.nlm.nih.gov/27647766/
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There is undoubtedly a lot more to it. But, the key idea is that iron has roles well beyond being a component of hemoglobin and allowing for oxygen delivery.
💥In fact, one study estimated that 6.5% of all human enzymes are iron-dependent!💥
pubmed.ncbi.nlm.nih.gov/30095136/
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➤Iron deficiency can lead to symptoms (e.g., fatigue) independent of hemoglobin
➤This results from iron's key role in many key human enzymes, particularly those required for mitochondrial function
➤Iron supplementation improves outcomes in heart failure
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