Rapid Responses to:

EDUCATION AND DEBATE: D Hugh Rushton, Robin Dover, Anthony W Sainsbury, Michael J Norris, Jeremy J H Gilkes, and Ian D Ramsay Why should women have lower reference limits for haemoglobin and ferritin concentrations than men? BMJ 2001; 322: 1355-1357 [Full text]

Rapid Responses: Submit a response to this article

Rapid Responses published:

Why equity is not simple

Vasiliy Vlassov   (1 June 2001)

Reply: Why equity is not simple

D Hugh Rushton   (4 June 2001)

If it’s not broken don’t fix it

Anne-Louise M Heath, Susan Fairweather-Tait, Mark Worwood   (9 June 2001)

Iron replete females have lower haemoglobin than males

Ian Morison, Elaine L Ferguson   (22 June 2001)

An observation in patients on renal replacement therapy

Vadamalai Vivek, Sunil Bhandari   (1 July 2001)

More on reference values for hemoglobin in women.

Wiveka E Elion-Gerritzen   (6 December 2001)

Why equity is not simple 1 June 2001
Vasiliy Vlassov, Professor Saratov Medical University Send response to journal: Re: Why equity is not simple	Dear Sir, Rushton D. H. et al. discussed the difference between blood hemoglobin concentrations between men and women only from the point of view of frequent iron deficiency in women. That is a serious simplification. E.g. blood hemoglobin concentration is influenced in men by sex hormones, and lower concentrations are described in healthiest men.1 Other factors have a play in producing this difference. The final argument - to use 'male' reference intervals for evaluation of blood tests obtained from women is not correct formally as well as practically. Formally, reference values for healthy people must originate from the healthy part of the same population. Practically, we do not have data supporting the hypothesis that the use of lower thresholds in diagnosis of anemia will lead to better health outcomes. But the load on laboratories and burden for physicians, as well as for patients, promise to be enormous. V. Vlassov 1. Vlassov VV. Changes in blood hemoglobin concentration of middle- aged healthy men. Milit.Med. 1999;164:311-5.
Reply: Why equity is not simple 4 June 2001
D Hugh Rushton, Honorary Senior lecturer University of Portsmouth Send response to journal: Re: Reply: Why equity is not simple	We were interested to receive and appreciate the response of Prof Vlassov about our article, to which we have the following reply. Sex hormones:- In children this is not an issue yet there is no sex difference in red blood cell count, haemoglobin (Hb) or ferritin concentrations. In menopausal women 10 years after they stop bleeding their Hb becomes comparable to aged matched men. However, testosterone levels of males aged >70 are significantly higher than their aged matched females. Further, in menstruating primates there is no sex difference in the lower values for HB (see table BMJ) or red blood cell count, in non-menstruating primates, there is no sex difference for Hb or red blood cell count, in both groups the males have significantly higher androgens concentrations. These data strongly suggests that testosterone has no significant impact on Hb production. A point supported from the fact that while androgens increase Hb levels in anaemic patients on renal dialysis they never achieve the levels obtained with erythopoietin. Healthy people :- 'Formally" :- Reference values are derived from populations considered to be healthy but as the UK government data (ref 9) shows, this assumption is invalid. For example, 90% of UK women of childbearing age do not attain the recommended level of iron from their diet. Consequently, blood parameters for haematological variables were derived from ‘apparently healthy’ populations which contained significant numbers of iron deficient females. A situation we believe occurs in many other countries. 'Practically' : - we disagree about the lack of data suggesting increasing the lower limits will not lead to better health outcomes. We believe there is widespread iron deficiency around the world and employing lower limits for menstruating women is masking this problem. Iron deficiency and iron deficient anaemia have well established, deleterious effects upon health, which resolve with iron supplementation and we would point Prof Vlassov to read refs 3, 23, 24, 25 for supporting data. For example, improved work capacity occurred in anaemic women upon iron supplementation before there was an increase in Hb concentration. We have no doubt women will be healthier with Hb levels comparable to males because they will be more likely to be iron replete. We appreciate that the impact of our hypothesis on laboratory costs and physician time will increase but the fact remains once these problems are corrected women will in all probability seek less medical help, be healthier and less of a cost burden!
If it’s not broken don’t fix it 9 June 2001
Anne-Louise M Heath, Postdoctoral Fellow; Head of Division; Professor Institute of Food Research, Norwich; *Dept of Haematology, University of Wales College of Medicine, Susan Fairweather-Tait, Mark Worwood Send response to journal: Re: If it’s not broken don’t fix it	EDITOR - Rushton et al. (1) suggest that male reference ranges for ferritin and haematological parameters should be used when assessing iron status in women of childbearing age. However, the authors make some incorrect assumptions and fail to consider the practical implications of such a change. No one disputes the fact that women need to have sufficient iron stores to prevent iron deficiency in the face of a physiological challenge such as pregnancy or blood loss. However, as far as we are aware there is no proven benefit to having a higher iron status. In fact, there may be some health risks. While suggestions that higher iron status may actually increase risk of coronary heart disease are now being questioned (2), there is evidence to suggest that a high iron intake may increase risk of colorectal cancer (3,4). Moreover, 1 in 150 (5) people in the United Kingdom are homozygous for the C282Y mutation of the HFE gene, which is associated with haemochromatosis. Although the clinical penetrance of this genotype appears to be lower than was originally thought, any widespread measures to increase the iron intake of women of child-bearing age are likely also to increase the intake of men and of postmenopausal women. It is therefore particularly important that any changes to the lower limits of iron status indices are firmly supported by clinical and experimental evidence. Haemoglobin response to a therapeutic trial of iron is the most reliable indicator of whether an individual has iron deficiency anaemia. Few studies have investigated haemoglobin response in women with haemoglobin greater than 115 or 120g/L because these women are not considered to be anaemic. However, one placebo-controlled trial in 43 women who had haemoglobin concentrations >120g/L, but who had serum ferritin concentrations <16mcg/L (i.e. iron depletion in the absence of anaemia) reported no increase in haemoglobin concentration following supplementation with 45mg elemental iron as ferrous sulphate three times a day for 8 weeks (6). Importantly, there was a significant increase in mean serum ferritin concentration, suggesting that iron deficiency anaemia was not present and that rather than increasing erythropoiesis, the additional absorbed iron was being stored. An alternative approach to test Rushton et al.’s hypothesis would be to interrogate haematological data collected from the adult National Diet and Nutrition Survey. If the mean haemoglobin concentration of men and women with similar serum ferritin values were not significantly different, this would lend support to their argument that women are a generally iron- depleted population. As far as we are aware, this analysis has not yet been done, and we are currently undertaking the exercise. Rushton et al. are incorrect in assuming that different lower limits for ferritin are used for detecting iron deficiency in young men and women. Reference ranges in healthy young adults certainly differ. For example, in non-anaemic, first-time blood donors of mean age 28 years (612 men, 890 women) the 95% ranges for serum ferritin were 35-220mcg/L for men and 9 to 136mcg/L for women (5). However, the limit for iron deficiency used by clinicians and epidemiologists is usually around 15mcg/L for both men and women (7). This value was originally established by determining the highest value found in patients with iron-deficiency anaemia (8). We agree with the authors that there may be functional effects associated with low serum ferritin concentrations, even in the absence of anaemia. However, these studies have only investigated the effects of serum ferritin concentrations less than 20mcg/L. They do not, therefore, provide evidence to support raising the lower limit of the reference range for serum ferritin. It is also important to ask what the practical implications would be of raising the lower limits for iron status indices in women to those applied to men. The median value for haemoglobin concentration in UK women of child-bearing age is 132g/L (9). Increasing the lower cut-off to 130g/L, in line with the male figures, would therefore define half the pre -menopausal adult female population of the UK as anaemic! How would the iron intake of all these women be increased? A recent dietary intervention study in 22 pre-menopausal women with serum ferritin <20mcg/L has shown that the highly motivated person who is mildly iron deficient may be able to use diet to improve their iron status (10). However, this study also showed that supplementation is likely to be a more practical option for most women because of the wide range of behavioural changes required in order to not just increase iron intake, but also increase the intake of iron absorption enhancers (such as meat and vitamin C-containing foods), and decrease intake of inhibitors (such as phytate in wholegrain cereals, and tannins in tea and coffee). Iron supplementation is known to produce unpleasant side-effects in a significant proportion of individuals, so any programme involving the use of iron supplements would be likely to have a detrimental effect on the well-being of a significant number of women. We believe that there is no evidence, at present, to support reclassification of haemoglobin and serum ferritin concentrations in women to normal values for men. Furthermore, we are unable to see how such a move could result in a positive outcome for women’s health and welfare with no related adverse effects. References 1. Rushton DH, Dover R, Sainsbury AW, Norris MJ, Gilkes JJH, Ramsay ID (2001) Why should women have lower reference limits for haemoglobin and ferritin concentrations than men? BMJ 322:1355-1357. 2. Danesh J, Appleby P (1999) Coronary heart disease and iron status: Meta -analyses of prospective studies. Circulation 99:852-854. 3. Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE, Zeleniuch-Jacquotte A, Akhmedkhanov A, Riboli E (1999) Iron intake, body iron stores and colorectal cancer risk in women: A nested case-control study. International Journal of Cancer 80:693-698. 4. Wurzelmann JI, Silver A, Schreinemachers DM, Sandler RS, Everson RB (1996) Iron intake and the risk of colorectal cancer. Cancer Epidemiology Biomarkers & Prevention 5:503-507. 5. Jackson HA, Carter K, Darke C, Guttridge MG, Ravine D, Hutton RD, Napier JA, Worwood M (2001) HFE mutations, iron deficiency and iron overload in 10,500 blood donors. British Journal of Haematology (In Press). 6. Zhu YI, Hass JD (1998) Response of serum transferrin receptor to iron supplementation in iron-depleted, nonanemic women. American Journal of Clinical Nutrition 67:271-275. 7. British Nutrition Foundation Task Force. Iron – Nutritional and Physiological Significance. London: Chapman and Hall, 1995. 8. Worwood, M. Serum ferritin. In: Iron in Biochemistry and Medicine, II. Edited by Jacobs A and Worwood M. London: Academic Press, 1980. 9. Gregory J, Foster K, Tyler H, Wiseman M. The Dietary and Nutritional Survey of British Adults. London: HMSO, 1990. 10. Heath A-LM, Skeaff CM, O’Brien SM, Williams SM, Gibson RS (2001). Can dietary treatment of pre-anaemic iron deficiency improve iron status? Journal of the American College of Nutrition (In Press).
Iron replete females have lower haemoglobin than males 22 June 2001
Ian Morison, Haematologist, Lecturer Southern Community Laboratories, Department of Human Nutrition, University of Otago, Elaine L Ferguson Send response to journal: Re: Iron replete females have lower haemoglobin than males	Rushton and colleagues1 propose that the high prevalence of iron deficiency among women resulted in the use of haemoglobin reference ranges which are lower than ideal and that male reference ranges should be used when assessing the iron status of females. To show that their conclusions are incorrect, we have used two independent sources of data to demonstrate that the long-recognised gender differences in haemoglobin reflect real physiological differences rather than the prevalence of iron deficiency. We have used specific exclusion criteria (ferritin, age, pregnancy) to ensure that the two gender groups were comparable and iron replete. The first data set, extracted from our community laboratory database, consists of 612 males and 1327 females aged 20-45 years all of whom have a serum ferritin value within the narrow range of 80 to 100 ug/L (indicating adequate iron status). The 10, 25, 50, 75 and 90th percentiles for males and females respectively were 139, 146, 152, 157, 163 and 123, 129, 135, 141, 146 g/L. To confirm these differences also existed in a community-based population, we provide data from the New Zealand National Nutrition Survey 1997/98 (NNS97) (described in ref 2), a random survey of 4636 New Zealand adults. From the survey population we selected all non-pregnant individuals aged 20-45 years with a ferritin between 50-100 ug/L and a normal C-reactive protein (to exclude individuals with anaemia due to chronic inflammatory conditions). The 10, 25, 50, 75 and 90th percentiles for males and females respectively were 140, 146, 150, 157, 160 (n=110) and 127, 131, 138, 142, 147 g/L (n=252). These results confirm our conclusion that the distribution of haemoglobin levels is substantially lower in females than in males. This analysis also shows, that depending on the choice of the lower limit of haemoglobin for males (usually between 130 and 135 g/L), 25-50% of women would be incorrectly classified as anaemic if a male reference range was used. This would have a profound public health impact due to indiscriminate diagnosis of poor iron status in women. With respect to ferritin, we agree that marked gender differences in "normal" population ferritin distributions occur because the iron requirements of menstruating women are higher and intakes lower than their male counterparts, resulting in lower iron stores among women 3. For ferritin, the lower limit of the reference range is more difficult to extract from population studies, and should perhaps instead be based on biological definitions of iron deficiency which include depletion of bone marrow iron stores. While, there is considerable debate in the nutrition literature regarding the appropriate ferritin cut-off value to use for defining iron deficiency 3 4 5, most would agree that gender-specific cut-offs are inappropriate for ferritin when defining iron deficiency. Ian M Morison, Haematologist Southern Community Laboratories, Dunedin, New Zealand, Elaine L Ferguson, Lecturer Department of Human Nutrition, University of Otago, Dunedin, New Zealand Email: ian.morison@sclabs.co.nz References 1. Rushton DH, Dover R, Sainsbury AW, Norris MJ, Gilkes JJ, Ramsay ID. Why should women have lower reference limits for haemoglobin and ferritin concentrations than men? BMJ 2001; 322: 1355-7. 2. Russell D, Parnell W, Wilson N, Faed J, Ferguson E, Herbison P, et al. NZ Food: NZ People. Key results of the 1997 National Nutrition Survey. Wellington: Ministry of Health, New Zealand Government, 1999. 3. Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA 1997; 277: 973-6. 4. Ferguson EL, Morison IM, Faed JM, Parnell WR, McKenzie J, Wilson NC, et al. Dietary iron intakes and biochemical iron status of 15-49 year old women in New Zealand: is there a cause for concern? N Z Med J 2001; 114: 134-8. 5. Hallberg L, Hulten L, Lindstedt G, Lundberg PA, Mark A, Purens J, et al. Prevalence of iron deficiency in Swedish adolescents. Pediatr Res 1993; 34: 680-7.
An observation in patients on renal replacement therapy 1 July 2001
Vadamalai Vivek, Specialist Registrar in Renal Medicine & Consultant Nephrologist. Department of Renal Medicine,Hull & East Yorkshire Hospitals NHS Trust, Anlaby Road, Hull, HU3 2JZ, Sunil Bhandari Send response to journal: Re: An observation in patients on renal replacement therapy	EDITOR- We read with interest the article by Rushton et al (1) about the reference limits for haemoglobin. We agree with the suggestion that the reference range of haemoglobin for women should be the same as that for men. Interestingly, in patients with renal failure having renal replacement therapy, the target haemoglobin to be achieved is the same in men and women (2,3). There is no reported difference in the erythropoietin requirements of men and women on renal replacement therapy. One factor, perhaps, contributing to the equality in haemoglobin concentration of the sexes could be the fact that many women on haemodialysis are amenorrhoeic(4). There is convincing evidence that aiming for a haemoglobin of 10-12 gm/dl improves morbidity and mortality in both men and women with renal failure undergoing dialysis(2,3). If the equivalent haemoglobin concentration is potentially equally beneficial for men and women with renal failure, one could, perhaps, view it to be similar for patients without renal failure. References: 1. D Hugh Rushton, Robin Dover, Anthony W Sainsbury, Michael J Norris, Jeremy J H Gilkes, and Ian D Ramsay- Why should women have lower reference limits for haemoglobin and ferritin concentrations than men? BMJ 2001; 322: 1355-1357. 2.Standards subcommittee of the Renal Association (1997). Treatment of adult patients with renal failure. Recommended standards and audit measures. Royal College of Physicians of London,London. 3.NKF-DOQI clinical practice guidelines for the treatment of anemia of chronic renal failure. Am J Kidney Dis 1997;30:Suppl 3:S192-S240. 4.Kawashima R. Douchi T. Oki T. Yoshinaga M. Nagata Y.- Menstrual disorders in patients undergoing chronic hemodialysis. Journal of Obstetrics & Gynaecology Research. 24(5):367-73, 1998 Oct.
More on reference values for hemoglobin in women. 6 December 2001
Wiveka E Elion-Gerritzen, clinical chemist Send response to journal: Re: More on reference values for hemoglobin in women.	Rushton et al. rightly pose the question why women should have lower reference limits for hemoglobin (Hb) and ferritin concentrations than men.(1) There is evidence that a) iron deficiency has not been taken into account while establishing reference values for Hb and ferritin, b) the lower limit of reference values for Hb in iron-sufficient women is > 130 g/l and c) women will benefit if this limit is applied instead of the current 120 g/l.(2) Reference limits for Hb presently in effect in most clinical laboratories do not take into account the frequently occurring iron deficiency in premenopausal women. Moreover, the limit for the diagnosis of anaemia recommended by the World Health Organisation (WHO), 120 g/l for women, has been established while excluding only the extreme iron-deficient group defined as follows: ferritin < 12 ug/l and/or transferrin saturation < 16 % and/or epp (erythrocyte protoporphyrin) > 70-100 ug/dl erythrocytes. A ferritin concentration < 12-15 ug/l is reportedly indicative of abscence of iron in the bone marrow. The WHO published the norms for Hb with the warning that they are an oversimplification: "Anaemia is defined as a condition in which the concentration is below the level that is normal for a given individualö and ôNormal values should be derived from a representative sample of healthy persons in whom presence of nutrient deficiency has been excluded." (3) The reference values published have however acquired the status of WHO-norms without this balanced appraisal. Iron supplementation in premenopausal women over a sufficient period of time results in Hb values equal to or over 130 g/l. In a study designed to establish reference values, both the anaemic and the control group showed Hb levels > 130 g/l after iron supplementation for 3 months with 180 mg daily. (4) In 3 other studies groups of women with iron deficiency without anaemia (Hb > 120 g/l) were treated. Iron suppletion of 60 mg weekly during 7 months (+ folic acid), 27 mg daily during 6 months and 120 mg weekly for 22 weeks resulted in Hb values close to or over 130 g/l.(5-7) Women will benefit from optimisation of their Hb level. Physical condition is directly proportional to Hb concentration. Energetic efficiency and endurance is affected at all levels of iron deficiency and there is increasing evidence from studies in animals and humans that iron deficiency affects voluntary activity.(8) In premenopausal women replenishment of iron stores beyond curing anaemia is of particular importance in view of the high requirements for iron during pregnancy. In industrialised countries an estimated 20-40 % of women have Hb levels < 130 g/l, in 70-80 % iron reserves are insufficient to meet the requirements of pregnancy.(9) This means that a majority of women needs supplementation and/or rigid dietary advise. One may object, these women do not complain. However fatigue is a complaint without a reference point and it is a well-known fact that slow onset anaemia is well tolerated, especially if the activity pattern can be adjusted. It should be aknowleged that Hb and ferritin measurements can detect an impairment of health that may, but more likely may not, be accompanied by subjective complaints. Wiveka E. Elion-Gerritzen, Ph D, clinical chemist Lange Kerkdam 58, 2242 BX Wassenaar, the Netherlands we@eliongerr.demon.nl Literature 1. Rushton DH, Dover R, Sainsbury AW, Norris MJ, Gilkes JJH, Ramsay ID. Why should women have lower reference limits for haemoiglobin and ferritin concentrations than men? BMJ 2001;322:1355-7 2. Elion-Gerritzen WE. Iron deficiency in premenopausal women and criteria for iron supplementation.(Dutch) Ned Tijdschr Geneeskd 2001;145:11-3 3. World Health Organization. Technical Report nr. 503. Nutritional anemiaÆs. Geneva:WHO;1972 4. Natvig H, Vellar OD. Studies on hemoglobin values in Norway 8. Hemoglobin, hematocrit and MCHC values in adult men and women. Acta Med Scand 1967;182:193-205 5. Viteri FE, Ali F, Tujague J. Long-term weekly iron supplementation improves and sustains nonpregnant womenÆs iron status as well or better than currently recommended short-term daily supplementation. J Nutr 1999;129:2013-20 6. Fogelholm M, Suominen M, Rita H. Effects of low-dose rion supplementation in women with low serum ferritin concentration. Eur J Clin Nutr 1994;48:753-6 7. Tee ES, Kandiah M, Awin N, Chong SM. School-administered weekly iron-folate supplements improve hemoglobin and ferritin concentrations in Malysian adolescent girls. Am J Clin Nutr 1999;69:1249-56 8. Haas JD, Brownlie T. Iron deficiency and reduced work capacity: A criticial review of the research to determine a causal relationship. J Nutr 2001;131:676S-690S 9. Milman N, Bergholt T, Byg, KE, Eriksen L, Graudal N. Iron status and iron balance during pregnancy. A critical reappraisal of i