Haemoglobin and ferritin concentrations in men and women: cross sectional study

Sirs,
Analysis of the data presented by Waalen et al[1]
reveals that 38% of women in the San Diego area are
iron deficient using a transferrin saturation level below
20% as an indicator of deficiency.

By focusing on the mean haemoglobin distribution
Waalen et al lost sight of a fundamental part of our
work[2]: Namely, why should women have lower
reference limits for haemoglobin and serum ferritin
concentrations than men? Our explanation for this
discrepancy was that a significant number of women in
the general population are iron deficient. Further, we
proposed that the lower reference limit for serum ferritin
(best predictor of body iron stores[3]) in menstruating
women has been incorrectly set lower than age and
weight matched males. If correct, and the Waalen et al
data[1] suggests we are, the lower female reference
limits for haemoglobin, red blood cell count, and serum
ferritin should be the same as for men.

Males have a higher mean haemoglobin value then
females. This is because they attain higher upper
limits. Thus if the range for men is 135g/L to 175g/L
their mean would be 155g/L while in women using the
same lower value (as we suggest) they would have a
mean of 145g/L (135g/L to 155g/L), which is a 10g/L
difference as Waalen et al found. A similar position is
seen in male primate data from the Zoological Society
of London, compared to their menstruating female
counterparts but unlike humans the lower limit of the
reference range does not significantly differ[4]. To
support their case Waalen et al cite a paper describing
one primate exception (Macaca fascicularis)[5].
However, this study included data from infants,
juveniles, and females half the age of the males and as
such cannot be taken as definitive or representative.
Further data analysis from the Zoological Society of
London for adult male and female macaques (males
109g/L to 161g/L versus 107g/L to 147g/L for
females[4]) supports our previous position: in which we
found no significant sex difference for the lower
haemoglobin reference limit.

Closer inspection of the Waalen et al serum ferritin
data[1] shows a large number of women ‘falling off’ the
lower end of the distribution. The haemoglobin
difference between the sexes was of the range 15 to
20g/L at the lower serum ferritin concentrations. This
cluster is a significant percentage (39%) of those who
had a serum ferritin level below the lowest male value
and as such cannot be ignored.

With reference to the Figure From Waalen et al[1] (Part C), the key feature is the significant number of women with
a serum ferritin below the lowest male value and the
haemoglobin intercept, which is below the accepted
lower limit for males (135g/L). The effect of such a large
number of iron deficient individuals will result in women
having a lower reference limit than men.

In part B of their paper[1], the transferrin saturation data
for 26-55 year olds also shows a significant difference
in the haemoglobin level of between 15 to 25g/L in
menstruating females with a transferrin saturation %
below 20 (the accepted cut off point for iron deficiency),
while in part D (>55 year olds) the difference is around
10g/L. This shows that 38% of menstruating women
(part B) and 29% of post-menopausal women (part D)
can be considered iron deficient. Taking the most
conservative position, the data from part B places 530
women (10% of the sample) as being ‘normal’ (Hb
>120g/L) who had transferrin saturations below 10%
and are undoubtedly iron deficient. Further, using the
male % transferrin saturation data in part B, 18% of
females had transferrin saturation levels below 15%
(the lowest male value) while in the post-menopausal
group (part D) 10% had transferrin saturations <_15. the="the" waalen="waalen" et="et" al="al" study1="study1" demonstrates="demonstrates" presence="presence" of="of" large-scale="large-scale" iron="iron" deficiency="deficiency" in="in" san="san" diego="diego" female="female" caucasian="caucasian" population="population" and="and" if="if" representative="representative" supports="supports" our="our" hypothesis="hypothesis" that="that" haematological="haematological" distributions="distributions" contain="contain" a="a" large="large" proportion="proportion" deficient="deficient" women.="women." p="p"/> The data showing a sex difference with age is more
complex than simply presenting mean values from
uncontrolled populations. Data from aged and weight
matched individuals of known health status, with
absolute ranges, medians, and mean values for
haemoglobin and serum ferritin concentrations would
be needed to address this issue.

We entirely agree that iron deficiency is important in
women’s health. However, Waalen et al do not address
the fact that there is no obvious biological requirement
for females to have a lower serum ferritin or
haemoglobin level than men, nor do they present any
arguments why this should be so. Man appears to
stand out from all other primates in this regard.
Population studies measuring haematological
variables may all be compromised by being sampled
from a population, which is assumed to be normal but
is biologically deficient and the data presented by
Waalen et al[1] actually supports this. Contrary to their
conclusion, our data does withstand scrutiny and we
would argue they supports our hypothesis that iron
deficiency is a significant and detrimental factor in
women presenting with a haemoglobin level below
130g/L. Further, we believe our advocacy to employ the
lower male reference limits for haemoglobin and ferritin
in women, is fully justified. After all in this context men
are non-menstruating women, haematologically
speaking!

References

1) Waalen J, Felitti V & Beutler E. Haemoglobin and
ferritin concentrations in men and women: cross
sectional study. BMJ 2002;325:137

2) 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 2001; 322: 1355-1357.

3) Beutler E, Felitti V, Ho NJ, Gelbart T. Relationship of
body iron stores to levels of serum ferritin, serum iron,
unsaturated iron binding capacity and transferrin
saturation in patients with iron storage disease. Acta
Haematol 2002;107 (3):145-9

4) Lynx. Haematological and Biochemical Data Base.
Institute of Zoology, The Zoological Society, London,
UK; January, 2000

5) Giulietti M, La Torre R, Pace M, Iale E, Patella A,
Turillazzi P. Reference blood values of iron metabolism
in cynomolgus macaques. Lab Anim Sci 1991;
41:606-608

Competing interests. None