Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseases
Guidelines on the Diagnosis and Management of IronDeficiency and Anemia in Inflammatory Bowel Diseases
Christoph Gasche, MD,* Arnold Berstad, MD,† Ragnar Befrits, MD, PhD,‡ Christoph Beglinger, MD,§Axel Dignass, MD, PhD,P Kari Erichsen, MD, PhD, Fernando Gomollon, MD,** Henrik Hjortswang, MD,††Ioannis Koutroubakis, MD,‡‡ Stefanie Kulnigg, MD,* Bas Oldenburg, MD, PhD,§§ David Rampton, DPhil,PPOliver Schroeder, MD, PhD, Ju¨rgen Stein, MD, PhD, Simon Travis, DPhil,*** andGert Van Assche, MD, PhD†††Key Words: guidelines, anemia, inflammatory bowel diseases, iron
Anemia is a common complication of inflammatory bowel dis-
eases. An international working party has formed and developedguidelines for evaluation and treatment of anemia and irondeficiency that should serve practicing gastroenterologists. Within a total of 16 statements, recommendations are made
Anemia in inflammatory bowel disease (IBD) is the most
common systemic complication of IBD.1-3 Several stud-
regarding diagnostic measures to screen for iron- and other
ies have addressed the epidemiologic, etiologic, or therapeu-
anemia-related deficiencies regarding the triggers for medical
tic aspects of this condition4,5; however, until now guidelines
intervention, treatment goals, and appropriate therapies. Anemia
for the diagnosis and management of anemia in IBD do not
is a common cause of hospitalization, prevents physicians from
exist. Anemia has great impact on the quality of life of
discharging hospitalized patients, and is one of the most frequent
affected individuals in addition to, but also independent of,
comorbid conditions in patients with inflammatory bowel dis-
IBD, but this topic has been omitted from previous (Ameri-
ease. It therefore needs appropriate attention and specific care.
can and European) IBD guidelines. Consequently, this group
(Inflamm Bowel Dis 2007;13:1545–1553)
of authors recognized the need for guidelines specific toanemia and IBD and set about developing them. The Britishguidelines on the management of iron deficiency anemia6
Received for publication July 31, 2007; Accepted August 17, 2007.
focused on the endoscopic approach for diagnostic purposes,
From the *Division of Gastroenterology and Hepatology, Medical University
rather than on IBD-related diagnostic or therapeutic guid-
of Vienna, Austria, †Institute of Medicine, Haukeland University Hospital,
ance. The goal of the current recommendations is to reduce
Bergen, Norway, ‡Department of Gastroentereology and Hepatology, Karolin-
the incidence of anemia, its severity, and need for blood
ska University Hospital, Stockholm, Sweden, §Division of Gastroenterology andHepatology, University Hospital, Basel, Switzerland, PDepartment of Medicine
transfusions in order to achieve a better quality of life and
I, Markus-Krankenhaus, Frankfurt, Germany, Surgical Clinic, Haugesund Hos-
reduced comorbidity in patients with IBD.7,8
pital, Haugesund, Norway, **Servicio de Aparato Digestivo, Hospital Clı´nico
Anemia in IBD has multiple causes (reviewed in Refs.
Universitario, Zaragoza, Spain, ††Division of Gastroenterology and Hepatology,
1,9), with iron deficiency being the most prevalent10 (Table
Linko¨ping University Hospital, Sweden, ‡‡Department of Gastroenterology,
1). Almost every anemic patient with IBD demonstrates some
University Hospital Heraklion, Crete, Greece, §§Department of Gastroenterol-ogy, University Medical Centre Utrecht, The Netherlands, PPDepartment Gas-
degree of iron deficiency11 as a consequence of dietary re-
troenterology, Barts and the London NHS Trust, London, UK, Division of
strictions, malabsorption, or intestinal bleeding.12,13 Iron de-
Gastroenterology and Hepatology, Johann Wolfgang Goethe University Medical
ficiency anemia occurs when iron stores are exhausted and
Center, Frankfurt, Germany, ***Gastroenterology Unit, John Radcliffe Hospital,
the supply of iron to the bone marrow is compromised. Iron
Oxford, UK, †††Department of Gastroenterology, University Hospital Gasthuis-berg, Leuven, Belgium.
deficiency anemia is a severe stage of iron deficiency in
Most of the authors have variously received unrestricted educational
which hemoglobin (or the hematocrit) declines below the
grants, consultancy fees, and/or hospitality from various pharmaceutical
lower limit of normal. Iron deficiency anemia is defined as
companies in the field of inflammatory bowel disease and anemia therapy.
anemia with biochemical evidence of iron deficiency. The
No author was paid for this work, nor did any company contribute to the
precise biochemical definition agreed on by the group is
Reprints: Prof. Christoph Gasche, AKH Wien, Gastroenterologie, Wa¨hr-
given below (see also Tables 2, 3). In active disease, inflam-
inger Gu¨rtel 18-20, A-1090 Vienna, Austria (e-mail: christoph.gasche@
matory mediators may alter iron metabolism (by retaining
iron in the reticular-endothelial system), erythropoiesis, and
Copyright 2007 Crohn’s & Colitis Foundation of America, Inc.
erythrocyte survival. This condition is termed anemia of
chronic disease (ACD).14 Many other causes of anemia exist
Published online November 2007 in Wiley InterScience (www.
in IBD but are generally less common (Table 1).
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
TABLE 1. Etiology of Anemia in Inflammatory Bowel Diseases TABLE 2. Minimum Hemoglobin and Hematocrit Levels Used to Define Anemia in People Living at Sea Level
Iron deficiencyAnemia of chronic disease
Folate deficiencyDrug-induced (sulfasalazine, thiopurines)
Purpose of the Guidelines
The principal purpose of this working group was to
the occasion of the United European Gastroenterolgy Week
provide simple guidelines for gastroenterologists (rather than
(UEGW) (2005 and 2006), Falk Symposium (2006) and the
hematologists or general practitioners) who care for patients
Digestive Disease Week (DDW) (2007). The first 2 meetings
with IBD. Since this was the first attempt to develop such
were used to discuss the various aspects of the topic. During
guidelines and because the quality and quantity of the liter-
the third meeting the guidelines process was initiated by
ature is limited, a certain amount of disagreement between
using a general questionnaire, which primarily circulated to a
experts was anticipated. If such disagreement persisted after
subgroup of 8 board members (A.D., K.E., C.G., F.G., I.K.,
detailed discussion, this is reported in the article.
B.O., D.R., O.S.) in February 2007. It was revised upon
The guidelines address the appropriate uses of diagnos-
response (March 2007) and finally voted upon in April 2007.
tic measures to screen for iron and other deficiencies related
The results of this process were presented at the final meeting
to anemia in IBD, discuss iron and other supplements to
and used as a basis for the decision process. In parallel, a
prevent and treat anemia in this context, and define therapeu-
comprehensive literature search was performed using
tic goals. The article is structured into 4 sections: evaluation
PubMed English-language articles or reviews (keywords: in-
of anemia in IBD; triggers for therapy; treatment targets; and
flammatory bowel disease or ulcerative colitis or Crohn’s
disease AND anemia or anaemia) by S.K. A secondary liter-
It is important to remember that these are guidelines,
ature was selected from literature references with regard to
not rules or protocols for blind adherence. The actual treat-
iron, vitamin B , folic acid, or erythropoietin. Parts of this
ment may vary on the availability of products, views of the
search (related to Crohn’s disease) were published previous-
patient, cost considerations, and the type of heath service.
ly.33 A preliminary document was drafted by C.G. and cir-culated to all board members. A revised document was
Development of Guidelines
agreed upon before submission to the journal. The process
The group was formed in 2005 by C. Gasche. Members
was independently supervised by Eduard Stange, Stuttgart,
were selected on the basis of their contributions to research in
whose contribution we gratefully acknowledge.
the area of anemia in IBD. Four meetings were held during
Grading of Recommendations
The guidelines conform to the North of England evi-
TABLE 3. Degree of Iron Deficiency Evaluated by Serum
dence-based guidelines development project.15 The grading
Ferritin or Transferrin Saturation in Adults
of each recommendation is dependent on the category of
evidence supporting it: Grade A requires at least 1 random-
ized controlled trial as part of a body of literature of overall
good quality and consistency addressing the specific recom-mendation (evidence level 1). Grade B requires the availabil-
Depleted iron stores in healthy adults or
ity of clinical studies without randomization on the topic of
consideration (evidence levels 2 or 3), or evidence from
extrapolation of evidence level 1. Grade C requires evidence
from a case– control study or from a nonindependent refer-
ence standard (evidence level 4) or evidence from extrapola-
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
tion of evidence levels 2 or 3. Grade D requires evidence
tration. More extensive workup should be performed if these
from expert committee reports or opinions or clinical expe-
investigations do not identify the cause of anemia, or if a
rience of respected authorities, in the absence of directly
therapeutic intervention is unsuccessful. More extensive
applicable clinical studies of good quality (evidence level 5).
workup includes serum concentrations of transferrin, vitaminB , folic acid, haptoglobin, lactate dehydrogenase, and cre-
1. Anemia Evaluation
atinine, a reticulocyte, and a differential white blood cellcount. Advice from a hematologist is appropriate if the cause
Definition of Anemia
of anemia remains unclear after more extensive workup
Statement 1A: The WHO definitions of anemia (Table
2) apply to patients with IBD. All patients with IBD should
Comment: Gastroenterologists tend to tolerate reduced
be assessed for the presence of anemia (Grade D).
hemoglobin levels better than their patients. As endoscopists,
Comment: It is well known that normal hemoglobin
they are commonly exposed to severe blood loss and very low
varies with age and gender, at different stages of pregnancy,
hemoglobin levels. The purpose of the current recommenda-
with altitude, smoking, and ethnicity.16 The correct interpre-
tions is to halt this complacency, to set an appropriate thresh-
tation of hemoglobin or hematocrit values, therefore, requires
old to trigger action, and to advise on necessary tests. The
the consideration of modulating factors in selecting appropri-
mean corpuscular volume (MCV) and mean corpuscular he-
ate cutoff values. The definitions of anemia in IBD is indif-
moglobin (MCH) are useful parameters and available within
ferent to other conditions and thus the WHO criteria apply.17
the complete blood count. Low MCV and MCH are clear
The recommendation that IBD patients should be regularly
indicators of iron deficiency. In areas with a high prevalence
assessed for the presence of anemia is based on its high
of beta-thalassemia, thalassemia traits should be excluded. In
prevalence, impact on the quality of life, and on morbidity.5
ACD, they may be normal or low.14 Macrocytosis is indica-tive of vitamin deficiency, but also arises from thiopurine
Screening Parameters
treatment (azathioprine or 6-mercaptopurine), other medica-
Statement 1B: Hemoglobin, serum ferritin, and C-reac-
tions, alcohol misuse, and hypothyroidism. Platelet and white
tive protein (CRP) should be used for laboratory screening.
blood cell counts are also available within the complete blood
For patients in remission or mild disease, measurements
count and help distinguish isolated anemia from pancytope-
should be performed every 6 to 12 months. In outpatients
nia. A truncated, soluble form of the transferrin receptor
with active disease such measurements should be performed
(sTfR) circulates in the plasma and its concentration is di-
at least every 3 months. Patients at risk for vitamin B
rectly proportional to the total body mass of cellular TfR.21 It
folic acid deficiency (e.g., small bowel disease or resection)
is largely influenced by the level of erythropoietic activity
need proper surveillance. Serum levels of vitamin B
and to a lesser extent by iron stores. sTfR is an excellent
folic acid should be measured at least annually, or if macro-
indicator of iron-deficient erythropoiesis, particularly helpful
in the differential diagnosis of iron deficiency (increased
Comment: The risk of developing anemia relates to
sTfR and low serum ferritin) versus inflammation (normal
disease activity, because both blood loss and ACD are trig-
sTfR and serum ferritin), or for detecting iron deficiency in a
gered by intestinal inflammation. Complete (or full) blood
patient with concomitant inflammation (increased sTfR and
count, CRP, and serum ferritin are minimum requirements to
normal serum ferritin).14 In clinical practice, however, sTfR
detect anemia, an inflammatory flare, or iron deficiency in an
is expensive and not available in many laboratories. There-
early stage. Diagnostic measurement of complete blood
fore, it was not included as a standard recommendation. Since
counts and CRP have been part of previous recommendations
disease activity is not always associated with an increase in
in IBD.18 The serum ferritin was added to these recommen-
acute phase proteins (particularly in ulcerative colitis) and
dations because iron deficiency is a prevalent nutritional
may not be accompanied by clinical symptoms, endoscopy
deficiency with a strong impact on anemia.39 The recom-
may be needed to evaluate disease activity in patients with a
mended timelines are based on expert opinion and reflect
common clinical practice, but do not apply to hospitalizedpatients. In patients with extensive small bowel resection,
Iron Deficiency
extensive ileal Crohn’s disease, or ileal-anal pouch, evidence
Statement 1D: Diagnostic criteria for iron deficiency
or folic acid deficiency should be sought more
depend on the level of inflammation (Table 3). In patients
without biochemical or clinical evidence of inflammation,appropriate criteria are a serum ferritin Ͻ30 g/L or TfS
Anemia Workup
Ͻ16%. In the presence of inflammation, the lower limit of
Statement 1C: Anemia workup should be initiated if the
serum ferritin consistent with normal iron stores is 100 g/L
hemoglobin is below normal. The minimum workup includes
serum ferritin, transferrin saturation (TfS), and CRP concen-
Comment: In IBD, the distinction between iron defi-
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
ciency anemia and ACD is important, since both conditions
Initiation of Iron Supplementation
typically overlap. Iron deficiency may be caused by contin-
Statement 2B: Iron supplementation should be initiated
uous blood loss from the ulcerated surface of the bowel,
when iron deficiency anemia is present (Grade A). For iron
malnutrition with reduced iron intake, or impaired iron up-
deficiency without anemia, different approaches to iron re-
take through the duodeno-jejunal mucosa. In the absence of
placement should be considered and discussed with the pa-
biochemical (CRP, leukocyte count) or clinical evidence (di-
tient. If patients are likely to develop iron deficiency anemia
arrhea, hematochezia, endoscopic findings) of inflammation,
the monitoring frequency should be increased (Grade D).
iron stores are likely to be zero if the serum ferritin is Ͻ30
Comment: Several randomized trials have tested the
g/L. In the presence of inflammation, serum ferritin levels
effect of iron therapy on patients with IBD-associated iron
can be high despite empty iron stores.22,23 In such cases, 100
deficiency anemia.28–30 The decision to supplement iron in
g/L is considered an appropriate cutoff level.14 During or
patients without anemia is more complicated and depends on
shortly after intravenous iron therapy, serum ferritin levels do
the clinical scenario, the patient’s history, and individual
not correlate with body iron stores.24 Iron deficiency may
preference. Oral iron would be a simple option. However, inIBD nonabsorbed ferrous iron has the potential to worsen
cause an array of clinical or subclinical symptoms such as
IBD symptoms and to aggravate intestinal inflammation
cognitive function or ovulatory fertility.25,26
through the Fenton reaction,* which releases reactive oxygen
Anemia of Chronic Disease
species.30,31 On the other hand, intravenous iron therapy may
Statement 1E: In the presence of biochemical or clinical
be considered inappropriately interventional, especially when
evidence of inflammation, the diagnostic criteria for ACD are
using iron dextran with its risk for dextran-associated ana-
a serum ferritin Ͼ100 g/L and TfS Ͻ16%. If the serum
ferritin level is between 30 and 100 g/L, a combination of
Initiation of Erythropoietic Therapy
true iron deficiency and ACD is likely (Grade B). Statement 2C: The use of erythropoietic agents is ef-
Comment: In patients with active IBD, certain cyto-
fective for the treatment of ACD and may improve the quality
kines or hepcidin may reduce iron absorption, retain iron
of life. It should be considered if the hemoglobin is Ͻ10.0
within cells of the reticular-endothelial system, and inhibit
g/dL or if there is no response to intravenous iron therapy
erythropoiesis.13 These mechanisms may lead to ACD, a
condition that is frequently found in hospitalized patients.50
Comment: Erythropoietic agents (such as epoetin alfa,
ACD is likely if the serum ferritin is Ͼ100 g/L and TfS
epoetin beta, darbepoetin alfa) are effective in the treatment
Ͻ16%. In addition, the sTfR/log serum ferritin may be a
of ACD at a hemoglobin below 10.0 g/dL.11,28,32 The actual
useful tool to exclude iron deficiency (if the ratio is Ͻ1).14
need for erythropoietic agents in this scenario is uncommon,because intravenous iron alone has a response rate of 70%–80%.28,33 Certain laboratory parameters such as the serum
2. Triggers for Treatment of Anemia
erythropoietin, sTfR, or transferrin levels may predict cases
Initiation of Therapy
that will not respond to intravenous iron alone and may profitfrom combination therapy.34
Statement 2A: Treatment should be considered for all
patients with a hemoglobin below normal. The decision to
Initiation of Vitamin Supplementation
initiate therapy depends on symptoms, etiology, and severity
Statement 2D: Replacement of vitamin B
of anemia, rate of change, comorbidity, and potential adverse
should be initiated if serum concentrations are below normal
Comment: The large variation of clinical scenarios
Comment: Measurement of serum folate and vitamin
(from borderline hemoglobin without iron deficiency to ex-
levels has many limitations and are not always reliable. In
tremely low hemoglobin levels, overt bleeding or to hemo-
the presence of macrocytosis or unexplained anemia, espe-
lytic anemia) requires an array of actions depending on the
cially in patients with ileal resection serum homocysteine and
clinical scenario and symptoms of the patient. The initiation
methylmalonic acid levels, should be measured.35
of therapy depends on individual symptoms (such as fatigue,
Blood Transfusion
headache, dyspnea, or palpitations), but also on disease ac-
Statement 2E: Indications for replacement of blood
tivity, overt bleeding, and hemoglobin levels. It is important
after acute or chronic gastrointestinal bleeding vary depend-
to consider that anemia impairs quality of life even in theabsence of specific symptoms7,27 and that its treatment leadsto improvement in the quality of life.28 These simple facts are
*The Fenton reaction is the iron–salt-dependent decomposition of hydro-
often unrecognized or neglected by gastroenterologists caring
gen peroxide, generating the highly reactive hydroxyl radical, possibly via an
oxoiron intermediate (Fe2ϩ ϩ H O 3 Fe3ϩ ϩOH ⅐ ϩ OHϪ).
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
ing on the clinical situation (including the rate of bleeding,
Treatment Evaluation
hemodynamic state, hemoglobin, age, concomitant disease)
Statement 3C: To evaluate the response to therapy,
and are best judged by the physician. Management should be
hemoglobin should be measured within 4 weeks in asymp-
directed at diagnosing and stopping intestinal bleeding. Blood
tomatic patients and sooner in symptomatic patients in order
transfusion is no substitute for the treatment of iron defi-
to adjust treatment accordingly. When monitoring oral iron
ciency anemia with intravenous iron, possibly in combination
supplementation, a serum ferritin above 100 g/L indicates
with erythropoietic agents. Should transfusion be judged nec-
appropriate iron stores. Serum ferritin is not useful for mon-
essary, iron replacement therapy is still required (Grade D).
itoring intravenous iron supplementation, but a TfS Ͼ50%
Comment: The need for blood transfusion should be
considered carefully, because most patients suffer from
Comment: Measurement of TfS falsely overestimates
chronic bleeding and repeated blood transfusions are not an
the therapeutic response to iron therapy because the increase
appropriate therapy for chronic blood loss. A principal pur-
in TfS is only temporary, for as long as oral or intravenous
pose of these guidelines is to reduce the need for blood
iron is being administered. In the setting of intravenous iron
transfusion by timely recognition and appropriate treatment
therapy serum ferritin levels are falsely high.24 In this situa-
of anemia. Options other than blood transfusion (including
tion a TfS Ͼ50% is the most useful indicator of iron over-
intravenous iron with or without erythropoietic therapy)
should always be considered and replacement of iron stores isnecessary even if the hemoglobin is corrected by transfusion. 4. Treatment of Anemia Iron Supplementation 3. Targets of Anemia Therapy Statement 4A: The preferred route of iron supplemen-
Treatment Goals
tation in IBD is intravenous, even though many patients willrespond to oral iron. Intravenous iron is more effective, better
Statement 3A: The goals of anemia treatment are to
tolerated, and improves the quality of life to a greater extent
increase the hemoglobin, serum ferritin, and TfS above the
than oral iron supplements (Grade A). Absolute indications
lower threshold of normal (Tables 2, 3), to prevent a further
for intravenous iron include severe anemia (hemoglobin Ͻ10
fall in hemoglobin, to avoid the use of blood transfusion, to
g/dL), intolerance, or inappropriate response (see Statement
relieve symptoms related to anemia, and to improve the
3B) to oral iron, severe intestinal disease activity, concomi-
tant therapy with an erythropoietic agent, or patient prefer-
Comment: Anemia is a frequent trigger for hospitaliza-
ence. Dosing and infusion intervals depend on the compound
tion and is a common factor delaying discharge from hospital.
(Table 4). Oral iron supplements can be used if absolute
Anemia is one of the most frequent comorbid conditions in
indications for intravenous iron therapy are not met. If oral
IBD-related mortality.36 It therefore needs appropriate atten-
iron is used, the response (Statement 3C) and tolerance
should be monitored and treatment changed to intravenous if
Response to Treatment
necessary (Grade C). Since side effects of oral iron are
Statement 3B: The erythropoietic response to iron or
dose-related, and because its absorption and efficacy are no
hematinic replacement is considered appropriate if the hemo-
greater when high doses are used, no more than 100 mg
globin concentration increases by at least 2 g/dL or reaches
elemental iron daily should be prescribed (Grade C).
normal (Table 2) within 4 weeks of treatment (Grade C). Comment: There are many factors in favor of intrave-
Comment: Human erythrocytes have a mean lifespan of
nous iron therapy. Clinical comparative trials29,37 show faster
about 120 days. This implies that Ϸ200 billion new erythro-
and prolonged response with intravenous iron. Oral iron may
cytes, carrying collectively 6 g of hemoglobin, are produced
not be able to compensate ongoing blood loss.32 Studies in
every day, i.e., 2–3 million new red cells every second. In
animal models of IBD demonstrate with consistency an in-
situations of anemia, which decreases oxygen supply, red cell
crease in oxidative stress, disease activity, intestinal inflam-
production can expand up to 20 times over baseline rates,
mation, and even colorectal cancer development through oral
underlying the very dynamic nature of erythropoiesis. Labo-
iron supplementation (reviewed in Ref. 4). This is not sur-
ratory methodology and fluid balance cause diurnal changes
prising, as about 90% of the ingested iron is not absorbed,
up to 1 g/dl. The 2 g/dL increase can be reached by intrave-
passes the sites of intestinal inflammation, and induces local
nous iron therapy within 2– 4 weeks.28,29 If the therapeutic
oxidative stress at sites of active inflammation (through the
response is inappropriate, treatment should be intensified
Fenton reaction, see above). Further studies indicate that
(oral iron switched to intravenous iron treatment), changed
nutritional iron may be one of the exogenous factors respon-
(addition of erythropoietic agents), or the cause of anemia
sible for the onset of colitis.38,39 In human IBD, oral iron
should be reevaluated (possibly with the assistance of a
induces oxidative stress,31 increases local disease activity,40
and its absorption is inhibited, possibly through a hepcidin-
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
TABLE 4. Intravenous Iron Compounds Chemical propertiesc MW [kD] Dosingb Test dose required Safety profiled Risk of dextran-induced anaphylaxis
n.a., Not available; MW, molecular weight. aAccording to Kulnigg (37) et al, 2007, Seid (54) et al, 2006. bPrescribing information of marketed products. cAccording to Crichton et al, 2005. (52)dAccording to Auerbach (41) et al, 2007, Chertow (53) et al, 2006. *Only in Europe.
mediated mechanism.13 The main factor in favor of oral iron
Erythropoietic Agents
is convenience, not efficacy. The inconvenience of intrave-
Statement 4B: Erythropoietic agents (Table 5) are ef-
nous iron is offset by the benefit in achieving therapeutic
fective for the treatment of ACD. To optimize the effect of
erythropoietic agents, treatment should be combined with
Various intravenous iron products are currently avail-
intravenous iron supplementation. Dosing and injection in-
able with differences in biochemical characteristics, side ef-
tervals depend on the compound used (Grade A).
fects, dosing, and country-to-country availability (Table 4). Comment: Erythropoietic agents are used for the treatment
High molecular weight iron dextran is obsolete, because of its
of ACD. Together with iron replacement, response rates of
potential to cause severe anaphylactic shock and associated
75%–100% have been reported in clinical trials.11,28,32,33,46,47
mortality.41 Ganzoni’s formula is useful to estimate iron
There are no dose-finding trials in IBD. Consequently, dosing
needs.42 In the IBD clinic, however, anemic patients will
and injection intervals are derived from treatment of other causes
rarely have a deficit less than 1000 mg. In fact, by using a TfSϾ
of ACD (such as cancer patients) (Table 5). In IBD studies,
50% as a guide to stop therapy (Statement 3C), 3600 mg
epoietin alfa has been used at 200 U/kg bodyweight twice per
iron sucrose has been administered safely in controlled trials
week32 or 150 U/kg bodyweight three times per week.28,33,46
without liver damage or iron overload.24,28 The risk of iron
Darbepoetin alfa has been tested in 1 study in IBD, with 0.9
overload can be considered very low in a population with
g/kg body weight once per week, a dose that might be con-
34 If oral iron is used, no reliable data
exist to prefer any one compound over another. Slow-release
sidered low.47 Erythropoietic agents should always be combined
products should be avoided as they are released beyond the
with intravenous iron supplementation because functional iron
area of iron absorption and may impact or cause ulceration at
deficiency is likely to develop.9 Functional iron deficiency is
Crohn’s strictures.43 The optimal dose of oral iron has still not
defined as an inappropriate availability of iron for erythropoiesis
been established. Since a maximum of 10 –20 mg of oral iron
despite normal body iron stores, which may be encountered
can be absorbed per day, higher doses are questionable.
during treatment with erythropoietic agents. In IBD, erythropoi-
Low-dose iron (100 mg elemental iron daily) is effective in
etic agents are considered safe. In general, subcutaneous admin-
istration is associated with fewer side effects and greater benefit.
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
properties profile Chemical
Inflamm Bowel Dis ● Volume 13, Number 12, December 2007
Adjustment of IBD Therapy
hemoglobin differences between blacks and whites. J Nutr. 1992;122:
Statement 4C: Azathioprine or 6-mercaptopurine (thio-
17. WHO, UNICEF, UNU. Iron Deficiency Anemia: Assessment, Preven-
purines) are not considered a cause of isolated anemia. Nev-
tion and Control. Report of a joint WHO/UNICEF/UNU consultation.
ertheless, for patients with pancytopenia thiopurines should
Geneva: World Health Organization; 1998.
be considered a cause and the dose adjusted appropriately.
18. Stange EF, Travis SP, Vermeire S, et al. European evidence based
consensus on the diagnosis and management of Crohn’s disease: defi-
Patients with a high MCV should be checked for vitamin B12
nitions and diagnosis. Gut. 2006;55(Suppl 1):i1–15.
and folate deficiency before macrocytosis is attributed to
19. Rath HC, Caesar I, Roth M, et al. [Nutritional deficiencies and complica-
tions in chronic inflammatory bowel diseases]. Med Klin. 1998;93:6 –10.
20. Duerksen DR, Fallows G, Bernstein CN. Vitamin B12 malabsorption in
Comment: Isolated anemia in patients on azathioprine
patients with limited ileal resection. Nutrition. 2006;22:1210 –1213.
or 6-mercaptopurine is unlikely to be caused by drug treat-
21. Beguin Y. Soluble transferrin receptor for the evaluation of erythropoi-
ment. Other causes should first be considered (Table 1). In
esis and iron status. Clin Chim Acta. 2003;329:9 –22.
22. Hansen TM, Hansen NE, Birgens HS, et al. Serum ferritin and the
some patients, however, a mild and asymptomatic reduction
assessment of iron deficiency in rheumatoid arthritis. Scand J Rheuma-
in hemoglobin may be seen. Precautions should be imple-
23. Bartels U, Pedersen NS, Jarnum S. Iron absorption and serum ferritin in
mented to avoid leukopenia or pancytopenia and the dose
chronic inflammatory bowel disease. Scand J Gastroenterol. 1978;13:
adapted accordingly.48,49 Although macrocytosis is regarded
as a feature of thiopurine therapy that has been suggested as
24. Ali M, Rigolosi R, Fayemi AO, et al. Failure of serum ferritin levels to
predict bone-marrow iron content after intravenous iron-dextran therapy.
a measure of appropriate dosing,50,51 vitamin B
deficiency should be excluded in patients with a macrocytosis
25. Bruner AB, Joffe A, Duggan AK, et al. Randomised study of cognitive
(Statement 1B) to avoid overlooking vitamin deficiency. Ap-
effects of iron supplementation in non-anaemic iron-deficient adolescentgirls. Lancet. 1996;348:992–996.
propriate treatment of the underlying disease is a key to
26. Chavarro JE, Rich-Edwards JW, Rosner BA, et al. Iron intake and risk
of ovulatory infertility. Obstet Gynecol. 2006;108:1145–1152.
27. Wells CW, Lewis S, Barton JR, et al. Effects of changes in hemoglobin
level on quality of life and cognitive function in inflammatory bowel
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VARIANTES GENÉTICAS Y METABOLISMO DE LOS OPIÁCEOS, LOS OPIOIDES Y LA COCAÍNA VARIANTES GENÉTICAS Y METABOLISMO DE LOS OPIÁCEOS, LOS OPIOIDES Y LA COCAÍNA DVM, BSC, DEA, MSC, MMB, MPHIL, PH.D DEPARTAMENTO DE CIENCIAS BÁSICAS DE LA SALUD LABORATORIO DE ENFERMEDADES METABÓLICAS. Algunas variantes en los genes que codi¿ can proteínas involucradas en el metabolismo o b
Allergen-induced Synthesis of F2-Isoprostanes in Atopic Asthmatics Evidence for Oxidant Stress RYSZARD DWORSKI, JOHN J. MURRAY, L. JACKSON ROBERTS II, JOHN A. OATES, JASON D. MORROW, LAURA FISHER, and JAMES R. SHELLER Center for Lung Research and Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tenessee It is thought that