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
Guidelines on the diagnosis and management of iron deficiency and anemia in inflammatory bowel diseasesGuidelines 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
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
Test dose required
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
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.
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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