Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial
BMJ 2003; 326 doi: https://doi.org/10.1136/bmj.326.7399.1124 (Published 22 May 2003) Cite this as: BMJ 2003;326:1124All rapid responses
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A raised serum ferritin in non-anaemic or even anaemic mothers is not a sole index of raised iron stores. Serum ferritin, frequently used as a marker of iron status in individuals, is also an inflammatory marker1. Serum iron concentration as measured by serum ferritin was also found to be increased in women with toxemia of pregnancy (mean 135 mcg/dl) compared to normotensive parturients (62 mcg/dl) and chronic hypertensive parturients (72 mcg/dl)2,3. In such cases Iron overload is associated with low levels of hepcidin, a peptide that regulates iron metabolism by triggering degradation of ferroportin, an iron-transport protein localized on absorptive enterocytes as well as hepatocytes and macrophages4. Therapeutics that could increase hepcidin levels or act as hepcidin agonists might help treat the abnormal iron absorption in individuals such as with β-thalassemia and related disorders4. Further, in case of inflammations, measuring soluble transferrin receptor may also be useful because an increased concentration is an indicator of iron deficiency5.
So hitherto erstwhile use of serum ferritin and transferrin saturation is become more challenging in the face of comorbidities/ inflammation in diagnosing iron deficiency. For instance, because serum ferritin is an acute-phase reactant and because the inflammatory state may inhibit the mobilization of iron from reticuloendothelial stores, the scenario of patients with serum ferritin >800 ng/ml, suggesting iron overload, and transferrin saturation <20%, suggesting iron deficiency, has been observed6. Thus, the use of serum ferritin and transferrin saturation in guiding iron therapy are insufficient then some of the newer alternative markers for iron status that may be useful, include reticulocyte hemoglobin content, percentage of hypochromic red cells, and soluble transferrin receptor, all of which have shown some promise in limited studies6. Finally, the role of hepcidin, a hepatic polypeptide, in the pathophysiology of iron mobilization is also to be kept in mind6.
Referrances:
1. Rambod M, Kovesdy CP, Kalantar-Zadeh K. Combined high serum ferritin and
low iron saturation in hemodialysis patients: the role of inflammation. Clin J Am Soc Nephrol. 2008 Nov;3(6):1691-701. Epub 2008 Oct 15.
2. Entman SS, Richardson LD, Killam AP. Altered ferrokinetics in toxemia of pregnancy: a possible indicator of decreased red cell survival. Clin Exp Hypertens B. 1983;2(1):171-8
3. Entman SS, Richardson LD, Killam APElevated serum ferritin in the altered ferrokinetics of toxemia of pregnancy. Am J Obstet Gynecol. 1982 Oct 15;144(4):418-22.
4. Gardenghi S, Ramos P, Marongiu MF, Melchiori L, Breda L, Guy E, Muirhead K, Rao N, Roy CN, Andrews NC, et al. Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice. J Clin Invest. 2010 Dec;120(12):4466-77. doi: 10.1172/JCI41717. Epub 2010 Nov 22.
5. Aimone-Gastin I. [Biochemical markers of iron status].[Article in French]. Nephrol Ther. 2006 Nov;2 Suppl 5:S321-6.
6. Wish JB. Assessing iron status: beyond serum ferritin and transferrin saturation. Clin J Am Soc Nephrol. 2006 Sep;1 Suppl 1:S4-8.
Competing interests: No competing interests
The report by Verdon, et al. showing the effectiveness of iron
supplementation in treating fatigue in non-anaemic women is an important
addition to the evidence that iron deficiency is a significant health
problem in women even apart from its effects on haemoglobin.1 As the
authors note, the results directly confirm those of a clinical trial that
we (Beutler) reported 40 years ago showing reduction of fatigue upon
treatment with iron among non-anaemic women with iron-depleted bone
marrow.2 We are puzzled, however, by their assertion that the trial they
now report was the first controlled one. Our trial design was a classical
double-blind crossover.
In reality, a syndrome of fatigue and other related symptoms
responsive to iron therapy in the absence of anemia has been documented
for more than 150 years [see references 2 and 3 for reviews]. More recent
reports have focused on effects on athletic performance. These studies
have shown that treatment with iron increased aerobic and anaerobic
capacity4 and decreased muscle fatigability5 among subjects having low
levels of serum ferritin and normal levels of haemoglobin at baseline.
Consistent among all of these reports is the relatively small (or absent)
effect of iron treatment on haemoglobin levels.
Further support of the clinical significance of non-anaemic iron
deficiency comes from our recent survey of iron status among a large
cohort of subjects attending a health appraisal center. In this study, a
significantly higher rate of fatigue, ¡°irritability,¡± and headaches was
reported by non-anaemic women with iron deficiency compared to iron-
replete controls (Table). The higher prevalence of these symptoms
persisted when the rather high cut-off for iron deficiency used by Verdon,
et al. (ie, serum ferritin <_50 ug="ug" l="l" was="was" applied.="applied." p="p"/> Although there appears to be consensus regarding the impact and
response to iron treatment, issues surrounding the diagnosis of non-
anaemic iron deficiency continue to be debated. We do not agree, however,
with Verdon et al.¡¯s assertion that their results indirectly support the
claim by Rushton that current reference ranges for haemoglobin and serum
ferritin are too low for women and should be changed to be the same as
that for men.6 We have previously pointed out that even among women with
relatively high levels of serum ferritin (>100 ug/L), mean haemoglobin
levels are 10-15 g/L lower than for iron-replete men, arguing against the
use of male references ranges for women.7
Attempts to refine references ranges for serum ferritin are unlikely
to improve detection of non-anaemic iron deficiency because the
variability of the normal range of this analyte is so great. More likely,
increased recognition and successful treatment of this condition will
result from a heightened awareness among clinicians of iron deficiency
apart from anemia as a possible cause of otherwise unexplained fatigue in
their patients. Thus, iron deficiency might be considered as part of the
differential diagnosis of fatigue, particularly in women with serum
ferritin in the lower end of the reference range, regardless of
haemoglobin levels. A trial of iron therapy for a limited period of time
in these patients would provide the diagnosis as well as the cure, and
seems quite free of risk.
Jill Waalen, MD, MPH*
Vincent Felitti, MD**
Ernest Beutler, MD*
*The Scripps Research Institute, La Jolla, California USA
**Kaiser Permanente, San Diego, California USA
Table. Prevalence of symptoms among white women with non-anaemic iron deficiency Symptom Subjects with Controls p¢Ó non-anaemic (=10,945) iron deficiency* (n=616) Fatigue or Severe Fatigue 208 (33.8%) 3,071 (28.1%) 0.0026 Irritability 118 (19.2%) 1,608 (14.7%) 0.0030 Frequent Headaches 155 (25.2%) 2,104 (19.2%) 0.0004 *Serum ferritin <_21 ug="ug" l="l" transferrin="transferrin" saturation="saturation" _16="_16" and="and" haemoglobin="haemoglobin" ã="ã" _120="_120" g="g" l.="l." _="_" serum="serum" ferritin="ferritin" ã21="ã21" ã16="ã16" ã120="ã120" ó="ó" chi-square="chi-square" pre="pre"/>
References
1. Verdon F, Burnand B, Fallab Stubi C-L, Bonard C, Graff M, Michaud
A, et al. Iron supplementation for unexplained fatigue in non-anaemic
women: double blind randomized placebo controlled trial. BMJ 2003;326:1124
-1130.
2. Beutler E, Larsh SE, Gurney CW. Iron therapy in chronically
fatigued, nonanemic women: a double-blind study. Ann Intern Med
1960;52:378-394.
3. Beutler E. History of iron in medicine. Blood Cells Mol Dis
2002;29:297-308.
4. Friedmann B, Weller E, Mairbaurl H, Bartsch P. Effects of iron
repletion on blood volume and performance capacity in young athletes. Med
Sci Sports Exerc 2001;33:741-746.
5. Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G,
Haas JD. Iron supplementation improves progressive fatigue resistance
during dynamic knee extensor exercise in iron-depleted, nonanemic women.
Am J Clin Nutr 2003;77:441-448.
6. Rushton DH, Dover R, Sainsbury AW, Norris MJ, Gilkes JJH, Ramsay
ID. Why should women have lower reference limits for haemoglobin and
ferritin concentrations than men? BMJ 322:1355-1357.
7. Waalen J, Felitti V, Beutler E. Haemoglobin and ferritin
concentrations in men and women: cross sectional study. BMJ 2002;325:137.
ACKNOWLEDGMENTS
This is manuscript number 15905-MEM. Supported by National
Institutes of Health grants DK53505-04 and RR00833 and the Stein Endowment
Fund.
Competing interests:
None declared
Competing interests: Table. Prevalence of symptoms among white women with non-anaemic iron deficiencySymptom Subjects with Controls p¢Ó non-anaemic (=10,945) iron deficiency* (n=616)Fatigue or Severe Fatigue 208 (33.8%) 3,071 (28.1%) 0.0026Irritability 118 (19.2%) 1,608 (14.7%) 0.0030Frequent Headaches 155 (25.2%) 2,104 (19.2%) 0.0004*Serum ferritin
Anemia is common in India to the tune of 60 percent of women, and
since it is too expensive to do iron and ferritin studies, it is
commonplace to make a clinical diagnosis and given 3 months of iron for
fatigue.Anemia is especially high in pregnancy, and as part of the
national anemia control program, 3 months of iron supplmentation is
routinely given to all pregnant women enrolled in the MCH rural
programmes, as it may not be possible to do HB testing.This government
policy is extermely useful.
Competing interests:
None declared
Competing interests: No competing interests
EDITOR - Vendom et al assessed the subjective response to iron
therapy in non-anaemic women of childbearing age.(1) They excluded
patients with haemoglobin level <117 g/l, in fact a cut-off point lower
than the one recommended by the World Health Organization (WHO) to define
anaemia. According to the WHO a woman should be considered anaemic when
her haemoglobin concentration is below 120 g/l.(2) The WHO definition of
anaemia, however, is open to criticism because it is mainly based on the
distribution of the haemoglobin values into the population. The existent
data indicate that, age, ethnic background and the presence of specific
symptoms, e.g., fatigue, should be taken into account, in addition to
haemoglobin level and gender, to define someone as anaemic.(3-5)
Among older (70 to 80 years) women, for example, haemoglobin of 135
g/l was found to be associated with significantly lower mobility
prevalence than haemoglobin of 120 g/l.(3) Additionally, Verdon et al
shows evidence that iron supplementation may decrease the intensity of
fatigue in women without anaemia by the WHO criteria, at least for younger
women of childbearing age. They also found that patients with lower
ferritin concentration had a higher likelihood to benefit from iron
supplementation. This study also supports a review of the criteria to
define anaemia, particularly anaemia due to iron deficiency. To better
guide therapeutic decisions, however, Verdon et al should inform if there
was a baseline haemoglobin concentration range where the effect of iron
supplementation on decreasing fatigue was more striking. It is also
interesting to report whether decrease in the degree of fatigue was
associated with a greater increase in the haemoglobin level among women on
iron replacement therapy.
References
1. Verdon F, Burnand B, Stubi CL, Bonard C, Graff M, Michaud A, et
al. Iron supplementation for unexplained fatigue in non-anaemic women:
double blind randomised placebo controlled trial. BMJ 2003;326:1124-7.
2. Nutritional anaemias. Report of a WHO scientific group. World Health
Organ Tech Rep Ser 1968;405:5-37.
3. Chaves PH, Ashar B, Guralnik JM, Fried LP. Looking at the relationship
between hemoglobin concentration and prevalent mobility difficulty in
older women. Should the criteria currently used to define anemia in older
people be reevaluated? J Am Geriatr Soc 2002;50:1257-64.
4. Johnson-Spear MA, Yip R. Hemoglobin difference between black and white
women with comparable iron status: justification for race-specific anemia
criteria. Am J Clin Nutr 1994;60:117-21.
5. Patterson AJ, Brown WJ, Powers JR, Roberts DC. Iron deficiency, general
health and fatigue: results from the Australian Longitudinal Study on
Women's Health. Qual Life Res 2000;9:491-7.
Competing interests:
None declared
Competing interests: No competing interests
Verdon et al. make clear that women will benefit from
replenishment of their iron stores. This study deserves
widespread attention.
Studies on the effect of iron on subjective complaints in
iron deficiency and iron deficiency anemia are indeed
scarce. On the other hand many data on improvement of
physical condition by iron treatment of iron deficient
anemic men and women (1-3) and iron deficient non-anemic
women (4) have been published. Objective criteria include
maximal physical achievement, endurance tests, hartbeat
frequency, VO2-max etc. Two studies report an increase in
voluntary activity after iron medication in addition to an
increase in productivity (3,5). Hence, men, women and
children will benefit conditionnally from optimization of
hemoglobin levels and iron stores. The reason that these
findings have not lead to a more active approach to
replenishment of iron stores and oxygen carrying capacity in
high risk groups in the Western countries is probably the
lack of a clear pattern of subjective complaints and
alleviation there-of after treatment. While it is a well
known fact that gradual onset anemia is well tolerated, that
patients adjust activity pattern and usually donot complain,
physicians wait for complaints to test hemoglobin and/or
ferritin levels. It should be realized that iron deficiency
and anemia are laboratory diagnoses. This leads me to the
question whether, despite the succes of the study, fatigue
is the right parameter-of-entry into a iron deficiency
anemia decision tree. What is the prevalence of iron
deficiency (ferritin<50 ug/l) without anemia (hemoglobin >
117 g/l) in women not complaining of fatigue in the Swiss
population?
Another remark concerns the fact that hemoglobin has not
been measured after treatment, leaving open the possibility
that a rise in hemoglobin also contributes to the better
score in the iron treated group. This is a fair probability
because the cutoff point for anemia in the study is low in
comparison with e.g. the WHO-limit for women of 120 g/l and
is certainly low in comparison to the lower limit of 129 g/l
(8.0 mmol/l) found in studies where iron deficient
non-anemic women were treated with iron (6-9). This does
however not affect the outcome of the study that women with
a ferritin concentration of <50 ug/l (85 % of the group
under study) have a positive subjective response to iron
treatment, even though the period of treatment, 1 month, is
relatively short.
1. Gardner GW, Edgerton VR, Senewiratne B et al. Physical
work capacity and metabolic stress in subjects with iron
deficiency anemia. Am J Clin Nutr 1977;30:910-7
2. Viteri FE, Torun B. Anaemia and physical work capacity.
Clin Hematol 1974;3:609-26
3. Edgerton VR, Gardner GW, Ohira Y, Gunawardena KA,
Senewiratne B. Iron-deficiency anaemia and its effect on
worker productivity and activity patterns. Brit Med J
1979;II:1545-9
4. Zu YI, Haas JD. Iron depletion without anemia and
physical performance in young women. Am J Clin Nutr
1997;66:334-41
5. Scholz BD, Gross R, Schultink W, Sastroamidjojo S.
Anaemia is associated with reduced productivity of women
workers even in less-physically-strenuous tasks. Brit J Nutr
1997;77:47-57
6. Viteri FE, Ali F, Tujague J. Long-term weekly iron
supplementation improves and sustains nonpregnant women’s
iron status as well as or better than currently recommended
short-term daily supplementation. J Nutr 1999;129:2013-20
7. Fogelholm M, Suominen M, Rita H. Effects of low-dose iron
supplementation in women with low serum ferritin
concentration. Eur J Clin Nutr 1994;48:753-6
8. Tee ES, Kandiah M, Awin N, Chong SM et al.
School-administered weekly iron-folate supplements improve
hemoglobin and ferritin concentrations in Malaysian
adolescent girls. Am J Clin Nutr 1999;69:1249-56
9. Elion-Gerritzen WE. Iron deficiency in premenopausal
women and criteria
Competing interests:
None declared
Competing interests: No competing interests
Dear sir,
We thank you for your comments on our paper. We do not pretend to be
the only group that has studied the relationship between iron depletion
and fatigue. The goal of the study was to examine if iron supplementation
was helpful in decreasing fatigue or tiredness in non anaemic women. As
stated in the discussion, we found several studies dealing with this
problem. Indeed, the study of Patterson et al has shown that both iron
rich diet and iron supplements can decrease fatigue (1). However this
study was neither randomised against placebo nor blinded. They compared
iron supplementation (ferrous sulfate 325 mg /day) vs advice to take an
iron rich diet. Our goal was to get a more definitive answer about the
effectiveness of iron supplementation to reduce tiredness in non anaemic
women complaining of fatigue, therefore we opted for a double blind
randomised placebo controlled trial.
Interestingly, you mentioned a very recent study (2) which was
published while our study was under review. This double blind randomised
placebo controlled trial assessed the effect of iron supplementation in
20 non anaemic iron depleted women (serum ferritin below 20 ug/l). The
outcome was muscle fatigue measured as the «maximum voluntary static
contraction with dynamic knee extension». The authors found that 10 women
who received 10 mg elemental FE as ferrous sulfate twice a day during 6
weeks decreased their muscle fatigability by 27% in comparison with women
who received placebo. However due to the low power of the study, this
improvement was not related to change in iron status. This study brings
however some additional evidence in favour of prescribing iron to
non–anaemic iron depleted women to reduce their fatigue.
We agree that because haemochromatosis may be present in women who
present with fatigue, iron supplementation should be given only after
control of the iron status.
In our study, very few side effects were observed, because of the low
dose of iron. The only patient who dropped out the study because of
gastrointestinal side effects was in the placebo group. No patient
received medication for constipation, so we do not think the problem was
very important in comparison with tiredness. Nevertheless, as for any
single intervention in healthcare, the potential benefits of a treatment
should be compared with the associated risks to insure that the indication
is appropriate.
Finally for those interested,we thank Dr Tony Helman, editor in chief
of the Arbor nutrition guide for his nice review of this subject which is
available online (3)
References
1.Patterson AJ, Brown WJ, Roberts DC. Dietary and supplement
treatment of iron deficiency results in improvements in general health and
fatigue in Australian women of childbearing age. J Am Coll Nutr. 2001 Aug;
20(4): 337-42.
2.Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G,
Haas JD. Iron supplementation improves progressive fatigue resistance
during dynamic knee extensor exercise in iron-depleted, nonanemic women.
Am J Clin Nutr. 2003 Feb; 77(2): 441-8.
3. Helman T. Iron and tiredness . Arbor clinical nutrition updates
2003 (May);159:1-3 ISSN 1446-5450. www. arborcom.com
Competing interests:
We are the authors of the study. Competing interests are already mentionned in the paper
Competing interests: No competing interests
Sir,
I read with interest the recent article by Verdon et al (BMJ, 24
May). Their observation that iron supplementation is useful in patients
with fatigue even in the absence of anaemia is an interesting one. I would
like to make three observations.
Firstly, studies of similar nature have been reported earlier. (1,2)
In a study by Brutsaet et al (1), 20 iron-depleted (serum ferritin<20
micro g/L), non-anaemic (>110 g/L) women were treated with iron or
placebo in a randomized controlled trial for six weeks and it was found
that iron supplementation resulted in a significant improvement in muscle
fatiguability. Patterson AJ et al (2) studied the effect of iron
supplementation or high iron diet in iron-deficient and iron-replete women
and found that both the groups (even the iron-replete group) improved in
terms of fatigue and measures of physical and mental health and vitality.
Authors have quoted this study (reference 15 of the article) as a non-
randomized trial, whereas in reality, it was a randomized controlled
trial. Hence, it is not fair for the authors to claim that they are the
first to think of this idea (as they have stated in discussion section).
Secondly, it needs to be stressed that all women with unexplained
fatigue should not be treated with iron supplementation. This is based on
the fact that haemochromatosis also presents with fatigue. Primary
haemochromatosis is considerably more prevalent than earlier believed.
Borch-Iohnsen B et al (3) noted that “as many as five per 1,000 of the
Norwegian population may have two mutated genes for haemochromatosis,
while up to 15% may be carriers of a single mutated gene, and for these an
extra intake of iron may be hazardous.” Hence, serum ferritin must be
known before initiating iron supplementation.
Lastly, adverse effects related to study drugs, if any, in the study
population, have not been mentioned. It would have been interesting to
note if some of the patients developed constipation, which could be more
bothering to them than fatigue itself!
References
1.Brutsaert TD, Hernandez-Cordero S, Rivera J, Viola T, Hughes G,
Haas JD. Iron supplementation improves progressive fatigue resistance
during dynamic knee extensor exercise in iron-depleted, nonanemic women.
Am J Clin Nutr. 2003 Feb; 77(2): 441-8.
2.Patterson AJ, Brown WJ, Roberts DC. Dietary and supplement
treatment of iron deficiency results in improvements in general health and
fatigue in Australian women of childbearing age. J Am Coll Nutr. 2001 Aug;
20(4): 337-42.
3.Borch-Iohnsen B, Hauge A. Should iron preparations be available
only by prescription? Tidsskr Nor Laegeforen 2001 Feb 10; 121(4): 460-2
(Abstract)
Competing interests:
None declared
Competing interests: No competing interests
Can someone please explain why such atoxic form of iron is still used
n medicinal iron formulations? Ferrous sulphate is the only salt form
identified with infant fatalities.
There are much safer forms available.
Also, can anyone please point me to any clinical studies that
demonstrate efficacy of such high levels of iron supplements compared to
levels between 20 - 30 mg per day?
Competing interests:
None declared
Competing interests: No competing interests
Re: Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial
The functional consequences of iron deficiency without anemia are not fully understood, despite a high prevalence in the United States and worldwide1. Studies show that fatigue can occur with iron deficiency without anaemia which may revert by iron supplementation2,3. On the other hand, a recently puiblished another study inferred that female blood donors with iron deficiency without anemia after a blood donation would not clinically benefit from iron supplementation4.
Iron is an indispensable element of hemoglobin, myoglobin, and cytochromes, and, beyond erythropoiesis, is involved in oxidative metabolism and cellular energetics. Hence, iron deficiency (ID) is anticipated to limit exercise capacity5. Myoglobin is an iron- and oxygen-binding protein found in the muscle tissue of vertebrates in general and in almost all mammals and is related to hemoglobin, which is the iron- and oxygen-binding protein in blood, specifically in the red blood cells6. The fatigue in the study that improved after iron supplementation may be due to deficiency in iron content of myoglobin and other enzymes and organelles like cytochrome without having iron deficiency anaemia (or without having overt iron deficiency) but having low levels of ferritin and transferrin ( in other words having latent iron deficiency).
More studies are required in asserting that latent iron deficiency ( or iron deficiency without anaemia) can cause fatigue. And its functional explanation is also required.
References:
1. Looker A, Dallman P, Carroll M, Gunter E, Johnson C. Prevalence of iron deficiency in the United States. JAMA 1997;277:973-6.
2. Pittori C, Buser A, Gasser UE, Sigle J, Job S, Rüesch M, Tichelli A, Infanti L.A pilot iron substitution programme in female blood donors with iron deficiency withoutanaemia. Vox Sang. 2011 Apr;100(3):303-11. doi: 10.1111/j.1423-0410.2010.01427.x. Epub 2010 Nov 23.
3. Pedrazzini B, Waldvogel S, Cornuz J, Vaucher P, Bize R, Tissot JD, Pecoud A, Favrat B. The impact of iron supplementation efficiency in female blood donors with a decreased ferritin level and no anaemia. Rationale and design of a randomised controlled trial: a study protocol. Trials. 2009 Jan 16;10:4.
4. Waldvogel S, Pedrazzini B, Vaucher P et al. Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: a randomized controlled trial BMC Med. 2012; 10: 8.Published online 2012 January 24. doi: 10.1186/1741-7015-10-8
5. Jankowska EA, Rozentryt P, Witkowska A, Nowak J, Hartmann O, Ponikowska B, Borodulin-Nadzieja L, von Haehling S,Doehner W, Banasiak W, Polonski L, Filippatos G, Anker SD, Ponikowski P.Iron deficiency predicts impaired exercise capacity in patients with systolic chronic heart failure. J Card Fail. 2011 Nov;17(11):899-906.
6. http://en.wikipedia.org/wiki/Myoglobin as accessed on 15/04/2012.
Competing interests: No competing interests