Anaemia and cigarette smoking

J. A. LEIFERT
Anaemia is a reduction in one or more of the major
red blood cell (RBC) measurements: haemoglobin
(Hb) concentration, haematocrit or RBC count. Ciga-
rette smoking has been associated with numerous
chronic diseases that can be complicated by anaemia.
For example, a number of different malignancies
(Groopman & Itri, 1999; Coifer et al., 2001; Harrison,
Shasha & Homel, 2002), as well as gastric or duodenal
ulcers (Peura et al., 1997), are responsible for a signi-
cant proportion of anaemia among smokers; the anae-
mia may result from blood loss (e.g. bleeding from an
ulcer) or from suppression of erythropoiesis by a
malignant tumour or chemotherapeutic treatment.
In healthy persons, however, cigarette smoking
causes an increase in Hb levels (Sagone & Balcerzak,
1975; Smith & Landaw, 1978; Northrop-Clewes &
Thurnham, 2006), probably mediated by exposure to
carbon monoxide (CO) (Goldman, 1976; Puente-Maes-
tu et al., 1998). Carbon monoxide binds to Hb carboxy-
haemoglobin (HbCO) which has a markedly reduced
oxygen-carrying capacity (Brody & Coburn, 1969; Col-
lier, 1976). HbCO causes a shift to the left of the disso-
ciation curve, resulting in a reduction in the ability of
Hb to deliver oxygen to the tissues. To compensate for
this decreased oxygen delivery, smokers maintain a
higher Hb level than nonsmokers (Goldsmith, 1967;
Smith & Landaw, 1978). Mean Hb levels and HbCO
levels increase progressively with the number of ciga-
rettes consumed per day (Nordenberg, Yip & Binkin,
1990). Cigarette smokers who smoke 40 or more ciga-
rettes per day have Hb levels that are, on average,
0.7 g/l higher compared with nonsmokers
(Nordenberg, Yip & Binkin, 1990). In addition to the
number of cigarettes smoked per day, the duration of
chronic exposure to HbCO also correlates with the
development of polycythaemia (Vanuxem et al., 1977).
Department of Haematology and
Oncology, University Medical
Centre, Freiburg, Germany
Correspondence:
J. A. Leifert, Department of Hae-
matology and Oncology, University
Medical Centre, Hugstetterstr.
55, 79106 Freiburg, Germany.
Tel.: +49 761 270 3401;
Fax: +49 761 270 3206; E-mail:
jens.leifert@uniklinik-freiburg.de
doi:10.1111/j.1751-553X.2008.01067.x
Received 6 March 2008; accepted
for publication 3 April 2008
Keywords
Anaemia, cigarette, smoking
SUMMARY
Cigarette smoking causes numerous diseases that are associated with
anaemia but the resulting low haemoglobin levels may be counter-
balanced by increased red blood cell production caused by chronic
exposure to carbon monoxide from cigarette smoke. Diverse mecha-
nisms are involved in inuencing the development or the course of
anaemic disease in smokers. This article presents an evaluation of the
current literature on the impact of cigarette smoking on various forms
of anaemia.
REVI EW ARTI CLE I NTERNATI ONAL J OURNAL OF LABORATORY HEMATOLOGY
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Journal compilation 2008 Blackwell Publishing Ltd, Int. Jnl. Lab. Hem. 2008, 30, 177184 177
Iron homeostasis appears to be affected mainly by
changing of Hb concentrations. Serum iron, transfer-
rin receptor and ferritin are mostly unaffected by
smoking, except in pregnancy where there is evidence
of increased erythropoiesis causing lower saturation of
plasma transferrin and some evidence of lowering of
iron stores (Kocyigit, Erel & Gur, 2001; Northrop-Cle-
wes & Thurnham, 2006). In addition, the slightly
reduced plasma volume may also contribute to the
increase in Hb levels detected in smokers (Siggaard-
Andersen et al., 1969; Smith & Landaw, 1978; Stones-
ifer, 1978). However, the elevated Hb level caused by
cigarette smoking may result in a masking effect on
the detection of anaemia. Nordenberg, Yip and Binkin
(1990) showed that among women of comparable
socio-economic status, the prevalence of anaemia is
4.8% among smokers compared with 8.5% among
individuals who have never smoked.
The increased Hb levels that result from tobacco
usage are, in general, reversible. In active smokers,
there is a strong correlation between HbCO and Hb
levels but healthy ex-smokers show no difference in
Hb levels compared with nonsmokers (Nordenberg,
Yip & Binkin, 1990). However, Hb levels may be con-
sistently elevated in long-term smokers, if they
develop pulmonary complications such as chronic
obstructive lung disease (COLD) (Vanier et al., 1963)
or pulmonary emphysema (Auchincloss & Duggan,
1957; Vanier et al., 1963) that lead to a chronic low-
ered oxygen blood saturation and subsequent poly-
cythaemia. The correlation between Hb levels and
smoking habits is less well dened in pregnant
women. Most studies show no signicant difference
in Hb levels between smoking and nonsmoking
women during pregnancy (Bureau et al., 1983; Nilsen
et al., 1984), perhaps because of an overall lower ciga-
rette consumption in pregnant women. However, foe-
tuses of mothers that continued smoking during
pregnancy, showed an elevated HbF as well as higher
haematocrit levels (Meberg et al., 1979; Bureau et al.,
1983).
HAEMOLYTI C ANAEMI A
Haemolysis induced by cigarette smoke (Minamisawa,
Komuro & Niki, 1990) or by constituents of cigarette
smoke, such as nitro methane (Natl.Toxicol.Program,
1997), has been demonstrated in animal models.
However, even though a possible correlation between
cigarette smoking and haemolysis has been proposed
(German, 1992), there are no conclusive data on the
induction of haemolysis by cigarette smoke in healthy
or diseased humans. For example, glucose-6-phos-
phate dehydrogenase (G6PDH) is increased in homo-
geneous leukoplakias of the oral mucosa. As smoking
has been implicated as an aetiological factor of leuko-
plakia, Hammar, Wettermark & Wladimiroff (1975)
measured G6PDH in the normal buccal epithelium
but no difference was found in the activity of G6PDH
between smokers and nonsmokers. In haemoglobin-
opathies such as Hb Zurich, which is associated with
haemolysis, CO may have a benecial effect on haem-
olysis: as a result of the 65-fold increase in the afnity
of the abnormal beta-globin chain of Hb Zurich for
CO, the molecule is stabilized and exhibits resistance
to oxidative injury, a decreased rate of haemolysis
and a marked increase in oxygen afnity (Virshup
et al., 1983; Zinkham, Houtchens & Caughey, 1983;
Zinkham & Winslow, 1989; Minamisawa, Komuro &
Niki, 1990).
Sickle cell disease (SCD) is the most common hae-
moglobinopathy and it too, can be affected by smok-
ing. Haemoglobin S results from the substitution of a
valine for glutamic acid as the sixth amino acid of the
beta-globin chain, which produces a Hb tetramer
(alpha2/beta S2) that is poorly soluble when deoxy-
genated. The polymerization of deoxyhaemoglobin
(Hb) S is essential to the vaso-occlusive phenomena
and haemolysis that are the clinical hallmarks of SCD.
Vaso-occlusion results in recurrent painful episodes
and a variety of serious organ system complications
that can lead to life-long disabilities and even death.
The Hb polymer assumes the form of an elongated
rope-like bre, which usually aligns with other bres,
resulting in distortion of erythrocytes into the classic
crescent or sickle shape and a marked decrease in red
cell deformability. Polymerization alone does not
account for the pathophysiology of SCD. Subsequent
changes in red cell membrane structure and function,
disordered cell volume control and increased adher-
ence to vascular endothelium also play an important
role. The resulting rheological defect is partially com-
pensated by a low haematocrit, which moderates the
rise in whole-blood viscosity (Berger & King, 1982).
The chronic haemolysis of SCD is usually associated
with a mild to moderate anaemia (haematocrit
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178 J. A. LEIFERT IMPACT OF CIGARETTE SMOKING ON ANAEMIA
2030%). Several factors may precipitate a sickle cell
crisis including dehydration, infection or cold weather;
the reduced oxygenation associated with cigarette
smoking may also cause a crisis in adolescents and
adults (Yale, Nagib & Guthrie, 2000).
SCD is associated with many complications, includ-
ing acute pulmonary disease, of which acute chest
syndrome is the most common form occurring in
approximately 3050% of patients. The clinical mani-
festations include chest pain, a new lesion on chest
radiograph and fever. It is the most frequently
reported cause of death in SCD adults and a risk factor
for early mortality. The usual aetiology is thought to
be vaso-occlusion but the main identiable causes for
acute chest syndrome are pulmonary emboli and
infectious bronchopneumonia (Vichinsky et al., 2000).
Acute chest syndrome is more frequent in smokers
(Young et al., 1992). The exact mechanism by which
smoking increases the frequency of acute chest syn-
drome is unclear but several possibilities may be con-
sidered. As stated above, carbon monoxide in cigarette
smoke displaces the oxygen from Hb-binding sites
resulting in a decreased oxygen-carrying capacity of
RBCs; this may exacerbate the tissue hypoxia in a dis-
ease where microperfusion may be already reduced
(Allred et al., 1989). Recurrent acute chest syndrome
(ACS) has been suggested to be a risk factor for
chronic lung dysfunction in SCD. Obstructive lung
dysfunction is fairly common in SCD. The increase in
respiratory resistance associated with acute chest syn-
drome is accompanied by an increase in diffusion
capacity. These changes are likely to be enhanced by
chronic bronchial obstruction resulting from long-time
cigarette consumption (Santoli et al., 1998). Moreover,
cigarette smoke-induced damage to vascular endothe-
lium and activation of coagulation (Kimura et al.,
1994; Celermajer et al., 1996) may further reduce tis-
sue microperfusion. In addition, the risk of cerebral
stroke, which is increased in SCD, may be further
enhanced by cigarette consumption (Bendixen, Posner
& Lango, 2001).
HbCO levels are frequently elevated in patients
with haemolytic anaemia. The elevated HbCO level in
SCD, as in other haemolytic diseases, is caused by an
increased haem catabolism (Sears, Udden & Thomas,
2001). The increase in endogenous HbCO production
(Sjostrand, 1949) is in close correlation with bilirubin
or number of reticulocytes and therefore correlates
with the extent of haemolysis (Sears, Udden & Tho-
mas, 2001). HbCO increases the afnity of other bind-
ing sites for O
2
. The shift in the dissociation curve has
the effect of reducing the level of deoxyhaemoglobin
and thus the tendency for HbS polymerization and
sickling (Roughton & Darling, 1944).
Sears, Udden and Thomas (2001) described a posi-
tive correlation between elevated HbCO levels and
percentage of irreversibly sickled cells. Their observa-
tion, however, may also be well explained by endoge-
nously elevated HbCO levels resulting from
haemolysis. This is supported by ndings that cigarette
smokers have an elevated level of HbCO compared
with nonsmokers but no correlation between HbCO
levels and vaso-occlusive severity could be detected
(Sears, Udden & Thomas, 2001). In contrast, West
et al. (2003) reported that children exposed to envi-
ronmental tobacco smoke showed more inpatient
sickle cell crises than unexposed patients. In addition,
the higher level of endogenously produced HbCO in
haemolytic anaemias, in comparison with healthy per-
sons may be even further increased by exogenous CO
absorbed from cigarette smoke.
Specic data on thalassaemia and cigarette smoking
are not available. However, similar to SCD, poor
peripheral oxygenation caused by low Hb levels and
endothelial dysfunction in thalassaemia (Aessopos
et al., 2006) may also be further reduced by pulmo-
nary or vascular damage resulting from chronic ciga-
rette consumption.
MEGALOBLASTI C ANAEMI AS
Folic acid levels in serum or RBCs seem to be reduced
in cigarette smokers, in both nonpregnant (Nakazawa
et al., 1983; Ortega et al., 1994; Cafolla et al., 2000;
Mannino et al., 2003; Stuerenburg et al., 2005) and
pregnant smokers (van Wersch, Janssens & Zan-
dvoort, 2002; Ozerol et al., 2004; Stark et al., 2005). In
addition, Piyathilake et al. (1995) demonstrated
decreased levels of folic acid and Vitamin B
12
in the
oral mucosa of smokers.
The risk of reduced RBC folate levels in smokers
is related to the number of cigarettes smoked per
day (Cafolla et al., 2000). One reason for the lowered
levels of folic acid might be an increased activity of
hepatic microsomal oxidases that are induced by
polycyclic aromatic carbon hydrates contained in
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J. A. LEIFERT IMPACT OF CIGARETTE SMOKING ON ANAEMIA 179
cigarette smoke; this could result in an enhanced
antipyrine clearance (Nakazawa et al., 1983).
Although some authors state that serum concentra-
tions of folate do not appear to be inuenced by
smoking, they concede that there may be some
inuence of dietary intake on concentrations of these
nutrients (Northrop-Clewes & Thurnham, 2006). For
example, compared with nonsmokers, smokers usu-
ally eat less whole wheat bread or high bre break-
fast cereals containing a high amount of folic acid
(Margetts & Jackson, 1993).
Although folate levels in serum or RBCs are
reduced in smokers compared with nonsmokers, it is
unclear whether this correlates with a higher inci-
dence in megaloblastic anaemias. However, Ortega
et al. (1994) demonstrated that cigarette smokers have
lowered folic acid levels as well as a higher median
corpuscular erythrocyte volume, indicating a possible
effect on haematopoiesis.
Although a reduction in folate levels has been
demonstrated in many publications, data on the inu-
ence of cigarette smoking on vitamin B
12
levels
remain inconsistent. The metabolism and excretion of
vitamin B
12
may be disrupted by cyanide contained in
tobacco smoke (Linnell et al., 1968) and elevated
homocysteine levels in smokers may be modulated by
different levels of B-vitamins (OCallaghan et al.,
2002) but vitamin B
12
levels do not seem to be consis-
tently altered. Most authors see no signicant differ-
ence in Vitamin B12 levels in smokers compared with
nonsmokers, either in nonpregnant or pregnant indi-
viduals (Wadia et al., 1972; Mansoor et al., 1997; Oz-
erol et al., 2004), although some studies show reduced
(Pagan et al., 2001; van Wersch, Janssens & Zan-
dvoort, 2002) or even raised levels of vitamin B
12
in
smokers (Tungtrongchitr et al., 2003).
Breakfast cereals may also be a valuable source of
vitamin B
12
for vegetarians but vitamin B
12
is mainly
found in foods like meat, eggs and milk products. In
addition, vitamin B
12
deciency does not develop as
rapidly as folate deciency. Normally, humans main-
tain a large vitamin B
12
reserve, which can last 2
5 years even in the presence of severe malabsorption
(Snow, 1999). This may explain why different die-
tary habits between smokers and nonsmokers (Larkin
et al., 1990; Margetts & Jackson, 1993) have a
greater effect on folate levels than on vitamin B
12
levels.
APLASTI C ANAEMI A AND HAEMATOXI CI TY
Many of the compounds found in cigarette smoke are
known to be haematotoxic. Benzene, for example,
has been associated with the induction of aplastic
anaemia (AA) (Smith, 1996; Velasco et al., 2001),
myelodysplastic syndrome (Pasqualetti et al., 1997;
Kane et al., 1999) and acute myeloid leukaemia
(AML) (Goldman, 1976; Rinsky et al., 1987; Medinsky
et al., 1996; Thomas & Chelghoum, 2004). In addition,
various possible leukaemogens other than benzene,
such as urethane, styrene, naphthalene, nitrosamines
or radioactive components may act through the pro-
duction of chromosomal defects (Hecht & Hoffmann,
1988; Wallace, 1989; McDonald et al., 2001).
Leukaemogenesis is recognized to be multifactorial
and not induced by single causal agents. Known risk
factors, such as genetic disorders, physical or chemical
exposure, exposure to radiation or chemotherapy,
exposure to viruses or antecedent haematologic dis-
ease account only for a small number of observed
cases (Sandler & Collman, 1987; Deschler & Lubbert,
2006). As different subtypes of AML may have a differ-
ent causal mechanism, Crane et al. (1996) suggested a
functional link between the pathogenesis of a specic
cytogenetic abnormality and the aetiological agent.
The development of myeloid leukaemia is a multi-
step process requiring the susceptibility of a haemato-
poetic progenitor cell to inductive agents at multiple
stages. Most cases of AML arise de novo without identi-
able leukaemogenic exposure (Deschler & Lubbert,
2006).
However, the correlation between cigarette smoke
and development of myeloid leukaemia is well docu-
mented (Kinlen & Rogot, 1988; McLaughlin et al.,
1989; Severson et al., 1990; Sears, Udden & Thomas,
2001). There is also evidence that the relative risk of
development of myeloid leukaemia is correlated with
the quantity of cigarette consumption (Kinlen & Ro-
got, 1988; McLaughlin et al., 1989; Brownson, Nov-
otny & Perry, 1993). It has been estimated that
smokers are exposed to signicantly higher concentra-
tions of benzene than nonsmokers (Wallace & Pellizz-
ari, 1987).
Although benzene exposure is clearly correlated to
the development of aplastic anaemia, data that corre-
late development of AA to cigarette smoke are
rare. Linet et al. (1989) failed to nd a signicant
2008 The Author
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180 J. A. LEIFERT IMPACT OF CIGARETTE SMOKING ON ANAEMIA
correlation between aplastic anaemia and cigarette
smoke in a case control study involving 59 patients.
One possible explanation is that the chronic exposure
to benzene may be enough to produce statistically sig-
nicant data on leukaemia. However, the quantity of
benzene taking up through cigarette smoking may be
too low to be measured on a basis of outcome for AA:
benzene-related AA occurs in heavily exposed ben-
zene workers who receive gram quantities on a daily
basis in more than one in 10 individuals (Smith,
1996). For individuals receiving hundreds of milli-
grams of benzene per day, the incidence decreases
approximately to 1 in 100. The ability to induce AA
then further drops with lower doses: in a large scale
study of 74 828 benzene-exposed workers and
35 805 unexposed controls, there were nine cases of
AA in the exposed workers group and none in
the unexposed group (Yin et al., 1996). In compari-
son, the average cigarette smoker has an uptake of
approximate 1.8 mg benzene per day (Wallace &
Pellizzari, 1987). Although the concentration is nearly
10 times the average daily intake of nonsmokers, this
dose may still be too low to show signicant differ-
ences in terms of induction of AA in small studies
with low numbers.
Cigarette smoking affects the incidence, as well as
the diagnosis of anaemia. Although a certain amount
of stabilization can be achieved in sporadic entities
like haemoglobinopathies, cigarette smoking in gen-
eral affects haematopoiesis in a negative way. By
inducing polycythaemia, the diagnosis of anaemia
may be hampered. The level of oxyhaemoglobin and
the rate of delivery of oxygen to the tissues are the
fundamental regulators of erythropoiesis (Grant &
Root, 1952). Although Hb levels are elevated in adult
smokers, Tanabe et al. (1997) found decreased levels
of erythropoietin in smokers compared with non-
smokers and suggested that production may be down-
regulated by an elevated red-cell volume. In contrast,
increased levels of erythropoietin were observed in
newborns of mothers who constantly smoked through
pregnancy (Varvarigou et al., 1994; Bili et al., 1996;
Yin et al., 1996; Gruslin et al., 2000).
The inuence of cigarette smoking on anaemia in
smokers may be further complicated by nonhaemato-
logical complications, such as reduced tissue oxygena-
tion caused by pulmonary or vascular alterations from
chronic tobacco consumption (Aronow, 1976; Aubry,
Wright & Myers, 2000). Therefore, it is essential to
better understand effects and mechanisms of cigarette
smoking in anaemic disease. It will be necessary to
evaluate the impact of cigarette smoke on anaemia in
further studies.
ACKNOWLEDGEMENTS
The author is grateful to J. L. Whitton and R. Feuer
for helpful comments on the manuscript.
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