Rapid Responses to:

PRIMARY CARE: F Verdon, B Burnand, C-L Fallab Stubi, C Bonard, M Graff, A Michaud, T Bischoff, M de Vevey, J-P Studer, L Herzig, C Chapuis, J Tissot, A Pécoud, and B Favrat Iron supplementation for unexplained fatigue in non-anaemic women: double blind randomised placebo controlled trial BMJ 2003; 326: 1124 [Abstract] [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Why use toxic salts?

Ron Law   (23 May 2003)

Iron Supplementation For Unexplained Fatigue In Non-Anaemic Women

Sudhir Kumar   (25 May 2003)

Re: Iron Supplementation For Unexplained Fatigue In Non-Anaemic Women

Bernard Favrat, François Verdon, Bernard Burnand   (1 June 2003)

Towards optimal iron stores and hemoglobin levels in premenopausal women!

Wiveka E. Elion-Gerritzen   (6 June 2003)

The WHO criteria for anaemia in women need revision

Antonio A Lopes   (7 June 2003)

Anemia the Indian experience in General Practice

vaishali m verma   (14 June 2003)

Greater Awareness of Non-anaemic Iron Deficiency Needed

Jill Waalen, Vincent Felitti and Ernest Beutler   (28 June 2003)

Why use toxic salts? 23 May 2003
Ron Law, Principal Beyond Alternative Solutions Send response to journal: Re: Why use toxic salts?	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
Iron Supplementation For Unexplained Fatigue In Non-Anaemic Women 25 May 2003
Sudhir Kumar, Consultant Neurologist, Department of Neurological Sciences, Christian Medical College Hospital, CMC Hospital, Vellore, Tamilnadu, India-632004 Send response to journal: Re: Iron Supplementation For Unexplained Fatigue In Non-Anaemic Women	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
Re: Iron Supplementation For Unexplained Fatigue In Non-Anaemic Women 1 June 2003
Bernard Favrat, Consultant of internal medicine, Medical oupatient clinic, University of Lausanne 1011 Lausanne, Switzerland, François Verdon, Bernard Burnand Send response to journal: Re: Re: Iron Supplementation For Unexplained Fatigue In Non-Anaemic Women	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
Towards optimal iron stores and hemoglobin levels in premenopausal women! 6 June 2003
Wiveka E. Elion-Gerritzen, clinical chemist Lange Kerkdam 58, 2242 BX Wassenaar, Netherlands Send response to journal: Re: Towards optimal iron stores and hemoglobin levels in premenopausal women!	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
The WHO criteria for anaemia in women need revision 7 June 2003
Antonio A Lopes, Associate Professor, Department of Medicine, Federal University of Bahia Rua Mar Floriano 448 apt 1301, Canela, Salvador, BA, CEP:40110-010, Brazil Send response to journal: Re: The WHO criteria for anaemia in women need revision	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
Anemia the Indian experience in General Practice 14 June 2003
vaishali m verma, GP Delhi India 110024 Send response to journal: Re: Anemia the Indian experience in General Practice	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
Greater Awareness of Non-anaemic Iron Deficiency Needed 28 June 2003
Jill Waalen, Research Associate The Scripps Research Institute, La Jolla, California USA 92037, Vincent Felitti and Ernest Beutler Send response to journal: Re: Greater Awareness of Non-anaemic Iron Deficiency Needed	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/L) was applied. 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/L, transferrin saturation <16%, and haemoglobin ¡Ã 120 g/L. ** Serum ferritin ¡Ã21 ug/L, transferrin saturation ¡Ã16%, and haemoglobin ¡Ã120 g/L ¢Ó Chi-square 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