The Journal of IHP
1
The Case for Blood Donation
Why Blood Donation is a Larger Health Issue than
Generally Appreciated By William R. Ware, PhD
William R Ware, PhD
Emeritus Professor, Faculty of Science
University of Western Ontario
warewr@rogers.com
Abstract
Blood donation is probably more often motivated by altruism than
by the notion that it carries health benefits. Iron is involved in many
biological processes. It is also well known to be a source of reactive
oxygen species (ROS) trough the Fenton reaction, and the result can be
oxidative stress with cellular, DNA, vascular and organ damage. The
currently used laboratory reference range for normal serum ferritin
typically covers from the 5th to the 80th or 90th population percentile
and is gender dependent. However, there is considerable evidence
that within this range adverse effects of iron are implicated, which
impact the development and progression of a number of common
disorders. There is also considerable data indicating that lowering
ferritin levels within the normal range to values corresponding to near
iron depletion produces beneficial results for a number of diseases.
In addition, oxidative DNA damage is strongly and significantly
correlated with ferritin levels within the normal reference range with
no apparent threshold. There appears to be no consensus as to what
constitutes an optimum level of iron body stores. However, there is a
large range of these stores between anemia and abnormal levels that
suggest intervention. It is suggested that optimum ferritin levels may
be at the low end of the normal reference range near the threshold for
anemia. The simplest and quickest way to dramatically lower ferritin
levels is blood donation.
April/May 2014 l www.ihpmagazine.com 51
Introduction
In the September 2013 issue of Integrated
Healthcare Practitioners, the potential toxicity
of iron and the connection between iron and
diabetes was explored (Ware 2013). While
not emphasized, elevated levels of serum
ferritin, a measure of iron body stores and
active iron, are associated with enhanced risk
for a number of disorders, and the levels from
which lowering produced clinical benefits
were well below the upper limit of the normal
reference ranges used internationally. In what
follows, this observation will be generalized to
a number of disorders and the question, “what
is the optimum serum ferritin level?” will be
addressed.
Hemochromatosis is not generally treated until
ferritin levels are considerably above these
upper limits of normal (Adams 2011).
The multiplicity of physiologic processes
involving ferritin, and in particular its role as
an acute phase reactant, has caused some to
question the use of serum ferritin as a marker
for the risk of various disorders (Adams 2012,
Lee 2004). However, as will be discussed, risk
of incidence of various disorders correlates
with ferritin levels in a large number of studies
with large sample size and a diversity of
disorders. More importantly, there are also a
number of disorders where lowering “normal”
ferritin by blood removal and driving ferritin
levels from above, near or even below the
population mean to near iron depletion
(threshold for anemia) produces significant
improvements in clinical manifestations or
markers.
Thresholds of ferritin levels and
risk of disease
Ferritin reference ranges and
levels regarded as normal
There is some variation in the upper reference
limits for serum ferritin that constitute a
threshold for concern. In North America,
typical values for the upper limit of normal
are 300-320 ng/mL for men, and 150-307ng/
mL for women. Similar values are common
in other regions. In a recent discussion of the
diagnosis of hyperferritinemia, the authors
indicate elevated ferritin levels are >300 ng/
mL for men and >200 ng/mL for women.
52 www.ihpmagazine.com l April/May 2014
In addition to the associations between ferritin
levels and diabetes discussed in the cited IHP
article, the following are of interest.
•In a study of men and postmenopausal
women, a ferritin threshold of >200 ng/mL
was associated with an increase in risk of a
first heart attack (Holay 2012).
•A study classified CHD-positive patients as
having one or more coronary arteries with ≥
50% blockage. Comparison of ferritin levels
revealed that those CHD-positive had on
average ferritin levels of 121 vs. 73 ng/mL for
those CHD-negative (Haidari 2001).
•At a ferritin threshold of >137 ng/mL,
increased risk of ischemic stroke was found
in a study of postmenopausal women (van der
A 2005).
Photo©iStockphoto.com
The variation of serum ferritin levels with
age and gender in the US can be obtained
from the Third National Health and Nutrition
Examination Survey (NHANES III)
(Zacharski 2000). For Caucasian men, the
mean serum ferritin at age 17-19 is about 60
ng/mL and by age 30-39 has a plateau at about
150 ng/mL where it remains until about age
60 when a steady decline to about 90 ng/mL
by age 90 is observed. For women, the mean
value is quite constant at around 30 ng/mL
until after menopause and then increases to
about 80 ng/mL by age 60 and then gradually
increases to about 100 ng/mL at age 80-90.
The Journal of IHP
• A ferritin threshold of 145 to 164 ng/mL was
found for increased risk of acute ischemic
stroke transforming to a hemorrhagic stroke
in older men and women (Choi 2012).
• A large study examined the association
between ferritin levels and laboratory
measured cardiovascular fitness (CVF) in
young men. The likelihood of the absence
of CVF, adjusted for numerous potential
confounders, became significantly apparent
at a ferritin threshold of >150 (Mainous
2009).
• Middle-aged men had significant risk of
developing hypertension, defined as BP ≥
140/90 mm Hg, at a ferritin threshold of >
146 ng/mL (Kim 2012).
Photo©iStockphoto.com
• A study of the relationship between increased
ferritin, oxidative stress and insulin
resistance in 151 healthy men revealed no
threshold, only continuous increases in
markers with ferritin levels from the first
tertile (≤97 ng/mL) to the third (≥180 ng/mL).
Notably, the correlations remained strong and
significant after adjustment for inflammation
(Syrovatka 2009).
• In a 5-year study the association between
ferritin levels and the incidence and
progression of carotid atherosclerosis was
examined among a cohort of 826 men and
women age 40 to 79 years. Serum ferritin
was found to be the strongest risk factor of
overall progression, and changes in ferritin
levels during follow-up modified the risk with
lower levels beneficial. The risk of incident
carotid atherosclerosis increased linearly
and doubled from quintile I (0-36 ng/mL) to
quintile IV (130-222 ng/mL). When subjects
with < 50 ng/mL of ferritin were compared
with those ≥ 50 ng/mL, the increase in
incidence of carotid atherosclerosis for
elevated ferritin per 100 person years was
approximately 0.3 vs. 4.8, 0.2 vs. 4.5 and 1.6
vs. 4.4 for men, premenopausal women and
naturally menopausal women, respectively
(Kiechl 1997).
• In a study of over 12,000 men, the ferritin
threshold for increased risk of any coronary
artery calcium was >257 ng/mL (Sung 2012).
• In a study of men from either northern
Europe (Zutphen) or the Mediterranean
south (Crete), mean ferritin levels were 134
ng/mL and 70 ng/mL, respectively. Those
from Crete (70 ng/mL) had consistently
lower levels of indicators of oxidative stress,
higher antioxidant capacity and higher
concentrations of major antioxidants than
men from Zutphen (Buijsse 2007).
Ferritin thresholds and benefit in
iron-lowering studies
The following studies are particularly important
since they appear less subject to confounding
than those cited above.
• In a randomized prospective trial, iron
reduction in male smokers with peripheral
arterial disease (PAD) reduced the risk of
death or nonfatal heart attack, such that the
number needed to treat with phlebotomy over
five years to prevent one acute event was only
eight, a very low number and uncommon
in clinical studies. Significant benefits were
also seen for all cause mortality, non-fatal
MI and stroke. The initial and final mean
ferritin levels were 125 ng/mL and 84 ng/
mL. In a larger study in which the above was
imbedded, unequivocal benefits for all cause
mortality, non-fatal MI and stroke were found
for iron reduction in younger individuals 4361 years of age including non-smokers, when
phlebotomy reduced ferritin levels to < 70 ng/
mL (Depalma 2012, Depalma 2013).
April/May 2014 l www.ihpmagazine.com 53
1
• A controlled trial involving phlebotomy
which decreased ferritin levels from a mean
of 188 to 105 ng/mL for a group of men and
women with the metabolic syndrome, found a
decrease in systolic blood pressure from 149
to 131 mm Hg, with no change in the control
group. Fasting blood glucose, HbA1c and
heart rate were also significantly decreased
(Houschyar 2012).
• Use of the oral prescription chelator
deferiprone over nine months in patients
with non-diabetic kidney disease reduced
ferritin from 144 to 59 ng/mL and resulted in
significant clinical improvements (Rajapurkar
2013).
• In a trial using phlebotomy in patients with
peripheral artery disease, a reduction in mean
ferritin levels from 122 to 74 ng/mL resulted
in a significant reduction in the incidence of
visceral malignancy (Zacharski 2008).
Comparison of both the above thresholds
for risk and the baseline ferritin levels from
which lowering produced benefit reveals an
incompatibility with the commonly used
reference range values regarded as normal and
of no concern.
Iron stores reductions and nonalcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD)
starts with simple hepatic steatosis and can
progress to non-alcoholic steatohepatitis
(NASH). One hypothesis for the pathogenesis
of this disorder is the involvement of iron
in increased oxidative stress and liver
inflammation (Nelson 2012). High ferritin
levels have been found independently
associated with advanced hepatic fibrosis
(Kowdley 2012). The following iron depletion
studies are thus of interest.
• A study of phlebotomy on an insulin resistant
group of patients with NAFLD and markedly
DONATION
HISTORY
PER YEAR
0
2
3
4
FERRITIN FERRITIN
MEDIAN RANGE
5-95 PCT*
137
46-396
44
17-122
38
14-110
31
12-91
* 5th to 95th percentile
54 www.ihpmagazine.com l April/May 2014
elevated ferritin levels showed a significant
reduction in insulin resistance (HOMA-IR
decreased from 4.81 to 3.12) when ferritin
levels were reduced from 438 to 52 ng/mL.
More importantly, alanine transaminase (ALT)
decreased from a mean of 58.1 to near normal
34.3 IU/L (Valenti 2007).
• A study examined the effect of phlebotomy
in either carbohydrate intolerant subjects
or type 2 diabetics, including some also
diagnosed with NAFLD based on elevated
ALT and ultrasound evidence of steatosis
(Facchini 2002). The NAFLD and nonNAFLD groups had baseline mean ferritin
levels of 299 and 220 ng/mL, respectively.
Phlebotomy produced near iron depletion
(ferritin 31-15 ng/mL) and ALT fell from 61
to 32 IU/L in the NAFLD group. There were
insignificant ALT changes observed in the
NAFLD-free group.
• In a study where ferritin levels were
manipulated with diet, 12 patients with
NASH were placed on a calorie, fat and iron
restricted diet. Baseline mean ferritin levels
were 280 ng/mL initially and 128 ng/mL at 6
months of intervention. ALT levels decreased
The Journal of IHP
from 104 to 42 IU/L over the same period.
Large changes were also seen in aspartate
aminotransferase (AST) levels (Yamamoto
2007)
Iron and oxidative damage
Urinary 8-hydroxydeoxyguanosine (8-OHdG)
is a reliable and frequently used biomarker
of systemic oxidative DNA damage (Nakano
2003, Valko 2006). The following studies are
of particular interest because of the apparent
absence of a threshold for adverse effects of
iron.
For over 500 healthy Japanese aged 21-67,
linear correlations between 8-OHdG and
ferritin were found, with Spearmen rank
correlation coefficients of 0.47, 0.76 and 0.73
for men overall, women aged less than 50, and
women 50 years or older, respectively. These
strong correlations were essentially unchanged
after adjustment for potential confounders.
Subjects exhibited a large range of ferritin
levels from near iron depletion to around 300
ng/mL for men and 100 ng/mL for women
(Hori 2010).
For a cohort of 2500 healthy individuals
aged 22 to 89 years, a smooth, almost linear
2.5 fold increase in 8-OHdG was found for
men as ferritin ranged from 10 ng/mL to
about 300 ng/mL. For women, 8-OHdG was
increased by a factor of 3 for ferritin levels
ranging from below 9 to 160 ng/mL (Nakano
2003). These results suggest no threshold and
this observation is consistent with a study of
vascular function and ferritin levels (Zheng
2005), and a study of oxidative stress and
insulin resistance (Syrovatka 2009).
In addition, a study of ferritin lowering with
phlebotomy was found to reduce 8-OHdG in
patients with chronic hepatitis C (Kato, 2001).
Another study found a beneficial impact of
reducing iron stores to near depletion on the
development of hepatocellular carcinoma
(HCC) from chronic hepatitis C (Kato 2007).
In both studies, final ferritin levels were about
10 ng/mL.
Influence of blood donation on
ferritin levels
Blood donation typically removes 450-500 mL
per visit. The following results from a large
sample of Danish men 30 to 66 years of age
illustrate the dramatic effect of blood donation
(Milman 1996).
Danish study of the influence of blood donation
of serum ferritin levels (ng/mL) in men, 30-66
years of age (Milman 1996).
These data are consistent with a recent
American study (Cable 2011). Thus on average
three to four donations per year will result in
a ferritin level mostly below 100 ng/mL with a
median representing near iron depletion.
Risks associated with blood
donation
Blood donation is not totally free of adverse
events. These include syncope, bruises and
haematomas and sensory changes. Syncope is
rare even among those over 40 (typically 0.05%
incidence). Others, while frequently of higher
incidence, are almost always transient and rarely
of significance. The incidence of permanent
injury has been cited as about 0.002% (Amrein
2012, Gavillet 2013, Newman 2012).
Of greater concern is the impact of frequent
donations on iron status. Deferral at blood
donor clinics is generally based on a finger
stick haemoglobin assay with a commonly
used threshold for deferral of < 12.5 g/dL,
a threshold that has been questioned (Cable
2011). The common lower limit for normal is
13.5 g/dL, and served as the older cut-off for
deferral. A 12- month multicenter donor clinic
follow-up study examined the iron status in
blood donors screened by finger stick. The
threshold for diagnosing unacceptable iron
stores was a ferritin level < 12 ng/mL. This was
found in 15% of those passing the haemoglobin
screening. The finger stick haemoglobin test is
evidently not excluding some individuals with
low iron status and thereby increasing the risk
of an adverse impact of donation. For frequent
blood donors, an annual ferritin test and if
appropriate, a follow-up test for iron deficient
erythropoiesis are indicated (Cable 2011).
Conclusions
It is clear from the above studies that the
serum ferritin thresholds for the appearance
of risk and the baseline values from which
lowering produces benefit are predominantly
well below the upper reference range values for
normal, and in fact more closely correspond
to population 50th percentiles. Indeed,
lowering ferritin to levels far below the 50th
population percentile produces significant
benefit associated with severity of a variety
of disorders. In some studies, this is observed
even when the baseline level for lowering
April/May 2014 l www.ihpmagazine.com 55
1
is already quite low. The DNA oxidative
stress studies strongly support the view that
the optimum ferritin level is one representing
near iron depletion, which can only be easily
achieved by blood donation or phlebotomy. This
conclusion challenges a widely held belief that
ferritin anywhere in the normal reference range
should not cause concern.
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