Anemia and IBD: Current Status and Future Prospectives

1. Introduction

Anemia is the most common systemic complication and extraintestinal manifestation of inflammatory bowel disease (IBD), particularly in Crohn’s disease (CD) patients [1–3]. Although it may be present anytime along the disease course, it is usually recognized at diagnosis and during flare‐ups. However, despite its major clinical relevance and quality of life (QoL) impact in both adult and pediatric IBD patients, it has been for long time neglected in this clinical setting [4].

Following the introduction in the last decade of new intravenous (IV) and oral iron therapies, IBD‐associated anemia (IBD‐A) has been deserving major attention from the scientific community. Furthermore, the increasing focus on extra‐digestive features of IBD, in parallel with the recent emergence of specific management guidelines concerning IBD‐A from the European Crohn’s and Colitis Organisation (ECCO) [5], has also contributed to a paradigm shift in the clinical approach of this clinical entity.

In fact, anemia in IBD is not just a laboratory marker; it is a complication of IBD that requires increased awareness and needs appropriate and timely diagnostic and therapeutic approaches. The impact of anemia on the quality of life of IBD patients is substantial, as it affects several aspects of quality of life, such as physical, emotional, and cognitive functions, work or school absenteeism, hospitalization rate, and health‐care costs [4, 6]. Thus, it seems to be reasonable that both in adult and in pediatric IBD patients, anemia should be recognized, comprehensively evaluated, and treated. Furthermore, not only a disease‐specific treatment has to be administered but in particular iron‐deficiency anemia should be treated, as there is a sound body of evidence demonstrating its beneficial impact in patients’ quality of life [4, 6].

2. Prevalence of anemia in IBD setting

The exact prevalence of IBD‐A is unknown [3, 4, 6]. Reported prevalence rates of anemia in IBD adult patients widely range from 6 to 74%, depending on the definition of anemia, the study design, the patient population considered (e.g., hospitalized patients versus outpatients), and the standards of screening and treatment [4, 6]. In a recent systematic review, the mean prevalence of anemia in adult patients treated in tertiary referral centers with CD was 27% (95% confidence interval 19–35) and 21% (95% confidence interval 15–27) for ulcerative colitis (UC) [6]. Not surprisingly, anemia is reported more frequently in hospitalized patients with IBD and occurs more frequently in CD as compared to UC. In fact, according to recent published studies, the calculated mean prevalence was 20% among outpatients and 68% among hospitalized IBD patients. Furthermore, women with CD are at a higher risk for anemia. It also appears that hemoglobin (Hb) concentrations increase in the years after diagnosis which may be explained by the remission of disease following successful medical or surgical treatment.

The currently used World Health Organization (WHO) definition of anemia (Table 1) applies also to patients with IBD [7–9]. As mentioned in the subsequent text, anemia in IBD is mainly the expression of a mixed pathogenesis with iron deficiency (ID) and anemia of chronic disease (ACD) as the most prominent factors, often coexisting [10]. However, ID is the most frequent cause, with a reported prevalence between 36 and 90% [4, 7]. Recent Scandinavian data in adults indicated the prevalence of iron deficiency anemia (IDA) at 20% and of isolated iron deficiency at 30% (without anemia). After treatment is stopped, IDA has been reported to recur after a 10‐month period and iron deficiency after 19 months after treatment [1–4].

Recognized limitations concerning most studies on the prevalence of IDA in patients with IBD are their retrospective nature or the fact of being surveys from referral centers. Recently, Ott et al. [10] have prospectively assessed the prevalence of IDA in a population‐based cohort at the time of first diagnosis and during the early course of the disease. A high prevalence of IDA at different points during the early course of disease was reported. At first diagnosis, anemia of chronic disease was predominant, whereas during follow‐up, iron deficiency became the most relevant reason of anemia. These findings are in line with data of other groups [4, 6], also describing a strong association between the severity of anemia and disease activity.

A possible explanation of these findings might be the population‐based character of Ott et al. study [10], as not only outpatients of a tertiary referral center were included in this study but also patients with less severe forms of IBD, which are mainly treated by their family doctors. In this setting, reasons for the insufficient response to the treatment might have been underdosing of iron supplementation, subclinical inflammation of the underlying disease, or lack of adherence of the patient. Surprisingly, only in one‐third of patients with proven anemia, further diagnostic approach was undertaken. Even patients with diagnosed iron‐deficiency anemia were infrequently and inconsequently treated with iron preparations, despite the high impact on quality of life.

Limited previous data suggest that anemia is more prevalent in children than in adults with IBD [7–10], although, to date, there have been no good comparative studies. Although anemia and iron deficiency might be at least as common in pediatric as in adult patients with IBD, the true prevalence in childhood is not known. In fact, IBD‐A has been recently estimated more common (about 70%) in children than in adults (about 30–40%) [10, 11]. In a recent cross‐sectional observational study, including pediatric and adult IBD patients, Goodhand et al. [11] found a prevalence of anemia of 70% (41/59) in children, 42% (24/54) in adolescents, and 40% (49/124) in adults (P < 0.01). Furthermore, children (88% (36/41)) and adolescents (83% (20/24)) were more frequently iron‐deficient than adults (55% (27/49)).

Recent population‐based studies have demonstrated that the phenotype of IBD presenting in the young patient differs from that of adult‐onset disease [5, 6]. Children and adolescents are more likely to be diagnosed with CD than UC, with a more severe and extensive disease distribution at presentation and more frequent extension of disease during the first 2 years [5, 6]. Since they tend to have more severe IBD, it has been hypothesized that the prevalence of anemia would be predictably greater in children and adolescents than in adults attending IBD outpatient clinics. Although in 2007, Gasche et al. have published the first guidelines on the diagnosis and management of iron deficiency and IBD‐IDA [12], only recently the first ECCO guidelines on the management of IDA and ID have emerged. Both guidelines concern IBD‐associated anemia, but no specific considerations on the treatment of pediatric IBD patients have yet been included [5, 13].

3. Pathophysiology of anemia

In the majority of cases, IBD‐A is mostly multifactorial, being a unique example of the combination of chronic ID and anemia of chronic disease (ACD) (Table 1) [4, 5]. Iron deficiency anemia occurs when iron stores are exhausted and the supply of iron to the bone marrow is compromised. IDA is a severe stage of ID in which hemoglobin (or the hematocrit) declines below the lower limit of normal (biochemical evidence of iron deficiency). The precise biochemical definition agreed on by the experts group is given below [5, 7]. In active disease, inflammatory mediators may alter iron metabolism (by retaining iron in the reticular‐endothelial system), erythropoiesis, and erythrocyte survival. This condition is termed anemia of chronic disease. Anemia due to iron retention in macrophages driven by pro‐inflammatory cytokines and hepcidin is also called functional iron deficiency (FID) [14–16].

Anemia in IBD (an particularly IDA) thus results (a) on the one hand, from low intestinal bioavailability of iron due to chronic intestinal blood loss from inflamed intestinal mucosa; (b) on the other hand, from the combination with impaired iron absorption, either as a consequence of malabsorption and/or short bowel syndrome, or as a consequence of inflammation‐driven blockage of intestinal iron acquisition and macrophage iron reutilization; (c) also, impaired dietary iron uptake might be involved, due to therapeutic or voluntary dietary restrictions and anorexia. Among other possible factors, intake of proton pump inhibitors, persisting H. pylori infection, may be additionally involved.

Other more rare causes of anemia in IBD include vitamin B12 deficiency (particularly after resection of the ileum), folate deficiency, and potential toxic effects of medications (such as proton pump inhibitors, sulfasalazine, methotrexate, and thiopurines; all these may aggravate anemia by negatively affecting iron absorption or erythropoiesis [5–7]. In fact, methotrexate and sulfasalazine interfere with the absorption of folate and may mediate folate deficiency [5–7]; sulfasalazine may also induce hemolysis or bone marrow aplasia; thiopurines and methotrexate can induce bone marrow toxicity in a minority of patients. Finally, other causes may include renal insufficiency, hemolysis, and innate hemoglobinopathies [5–7].

The average adult harbors at least 3–4 g of stored iron that is balanced between physiologic iron loss and dietary intake. Most iron is incorporated into hemoglobin, whereas the remainder is stored as ferritin, myoglobin, or within iron‐containing enzymes. It is estimated that about 20–25 mg of iron is needed daily for heme synthesis; approximately 1–2 mg of this requirement comes from dietary intake and the remainder is acquired from senescent erythrocytes (recycling) [8, 9]. Total iron loss averages about 1–2 mg/day, mostly via fecal losses, skin, and intestine cellular desquamation, as well as through menstruation.

Body iron homeostasis is finely regulated by multiple and sophisticated mechanisms, the interaction of the liver‐derived peptide hepcidin with the major cellular iron exporter ferroportin [15–17] being of major relevance. The synthesis and release of hepcidin are induced by iron loading and inflammatory stimuli such as interleukin 1 (IL‐1) or IL‐6, whereas its synthesis is blocked by ID, hypoxia, and anemia. Hepcidin targets ferroportin on the cell surface (enterocytes and macrophages), resulting in ferroportin internalization and degradation and blockage of cellular iron entry. Low circulating hepcidin levels enable an efficient transfer of iron from enterocytes and macrophages to the circulation, aiming to overcome ID; on the other hand, iron is retained in these cells when hepcidin levels are high and serum iron levels drop [15–17].

Furthermore, inflammatory cytokines can directly inhibit iron absorption and stimulate the uptake and retention of iron in macrophages via hepcidin‐independent pathways. Interestingly, there is clinical evidence that circulating hepcidin levels have an impact on the efficacy of oral iron therapy and can predict its nonresponsiveness; this is consistent with experimental data demonstrating reduced intestinal ferroportin expression and iron absorption in individuals with increased hepcidin levels primarily due to inflammation [17]. As a result, anemia develops and is characterized by low circulating iron levels and an iron‐restricted erythropoiesis in the presence of high iron stores in the reticuloendothelial system, reflected by normal or high levels of ferritin.

Hepcidin expression mediated through cytokine and the direct effects of cytokines on iron trafficking in macrophages play a decisive role in the development of this type of anemia (i.e., ACD or the anemia of inflammation), by retaining iron in the reticuloendothelial system and blocking iron absorption, which results in an iron‐limited erythropoiesis [15,16]. This is reflected clinically by a reduced transferrin saturation (value below 16–20%). In addition, cytokines and chemokines further contribute to anemia by negatively affecting the activity of erythropoietin and an inflammation‐driven impairment of erythroid progenitor cell proliferation [15–17].

As previously mentioned, patients with active IBD may have true ID due to chronic blood loss, as reflected by low ferritin levels. Moreover, true ID and anemia reduce hepcidin expression. These effects drive an iron‐deficiency‐mediated inhibition of SMAD signaling in hepatocytes and erythropoiesis‐driven formation of hepcidin inhibitors such as erythroferron and growth differentiation factor 15 (GDF‐15) [15, 16]. Thus, in the presence of both inflammation and true ID, circulating hepcidin levels decrease because inflammation‐driven hepcidin induction is largely regulated by anemia and ID. Therefore, in truly iron‐deficient patients, despite the presence of systemic inflammation, considerable amounts of iron might still be absorbed from the intestine.

4. Diagnostic criteria and differential diagnosis

As stated, in IBD patients, anemia is often multifactorial, being IDA, the most common cause. ACD is also an important etiology, and usually is associated with poor disease control or severe disease. Other causes contributing to anemia in IBD include vitamin B12 and folic acid deficiency as well as adverse effects of certain drugs (salazopyrine sulfasalazine and azathioprine). In both adult and pediatric patients with IBD, other chronic conditions should also be considered (i.e., renal insufficiency, hemolysis, and innate hemoglobinopathies).

In pediatric‐IBD setting, other mechanisms of IDA, non‐IBD related, must be considered, as this is a high‐risk group of ID and IDA, namely characterized by high growth periods, insufficient ingestion due to dietetic choices, parasitic infestations, low socioeconomic level, and migrant families. It should also be noticed that ID in the absence of anemia is more common than IDA, as normal Hb levels do not necessarily mean adequate iron stores [5, 7].

World Health Organization anemia definition (Table 2) is considered valid in both adult and pediatric patients with IDA and current ECCO guidelines recommend its application to the establishment of anemia diagnosis.

Hemoglobin levels are influenced by age, gender, pregnancy, ethnicity, altitude, and smoking habits. Interpretation of Hb and hematocrit levels should take these factors into account.

All patients with IBD should be screened regularly for anemia, especially in the presence of active disease, as ACD can coexist with IDA. The initial workup to establish anemia diagnosis (and to differentiate IDA from ACD) should include complete blood count, C‐reactive protein (C‐RP) or erythrocyte sedimentation rate (ERS), serum ferritin, and transferrin saturation. A mean corpuscular volume (MCV) and reticulocytes are also helpful in the classification and differential diagnosis of anemia in IBD setting (Table 3). In some situations, microcytosis and macrocytosis may coexist, neutralizing each other and resulting in a normal MCV. In this case, a wide size range of the red cells (red cell distribution width) (RDW) is an indicator of ID, further contributing to the differential diagnosis. Platelet and white blood cell counts, also available within the complete blood count, are important to distinguish isolated anemia from pancytopenia.

By definition, IDA presents as anemia associated with low serum ferritin (referred as the most important laboratory parameter in the definition of IDA), low serum iron, low transferrin saturation, and elevated total iron‐binding capacity. Other hematological parameters, such as RDW, mean corpuscular volume, and mean corpuscular hemoglobin (MCH), might also contribute to IDA diagnosis; high RDW, low MCV, and MCH corroborate IDA. These parameters may be normal in ACD. In the presence of inflammation (such as acute exacerbation or poorly controlled disease), it should be recognized that ferritin levels are usually high. New promising markers, such as a soluble form of transferrin receptor (elevated in iron deficiency despite the presence of inflammation) are particularly helpful in the presence of active disease, being currently available in some centers [17]. Other markers, such as serum hepcidin and red blood cell size factor, may further contribute to differential diagnosis of IDA and ACD [15, 16].

Currently, it has been proposed that, in the absence of inflammation/active disease, serum ferritin levels of <30 μg/L reflect depleted iron stores; during active disease, serum ferritin levels of <100 μg/L should be considered as depleted iron stores. In both settings, transferrin saturation of <16% has been associated with poor iron stores. IDA should be considered in the presence of elevated inflammation parameters and normochromic and normocytic anemia or microcytic and hypochromic anemia with serum ferritin of >100 μg/L.

If, after initial workup, the cause of anemia remains unclear, other tests should be performed according to the most plausible cause of anemia, such as determination of serum B12 vitamin, folic acid, blood smear, haptoglobin, lactate dehydrogenase, urea, creatinine, and electrophoresis of Hb [5].

5. Evolving treatment strategies

6. Prevention

The recurrence of IDA in IBD is well recognized, occurring in about 50% of the adult patients within 10 months after IV iron treatment [5, 7, 44, 45].

Recurrence of IDA is directly related with iron replenishment at the end of IV iron treatment [5, 44–46]. It is admitted that ferritin levels over 400 µg/L might prevent recurrence of IDA in the subsequent 1–5 years.

ECCO guidelines state that IBD patients should be monitored for recurrent iron deficiency every 3 months for at least 1 year after correction, and between 6 and 12 months thereafter [5]. Furthermore, they highlight that recurrence might be associated to persistent intestinal disease activity even if there is clinical remission and remission in inflammatory parameters. An important message is that recurrence of anemia, especially in the setting of ACD, should lead to the evaluation of disease activity and an optimized treatment strategy would be required, as disease control is usually sufficient to correct anemia.

Data concerning recurrence of IDA in pediatric patients are scarce; however, considering the high prevalence of pediatric IBD‐IDA anemia, a recurrence rate similar to that reported in adult patients should be expected. So far, these data were only described in one study [41], in which six of 19 (30%) patients needed re‐treatment within the 40 months of follow‐up (median period of 15.5 months). Re‐treatment was proposed when Hb levels fell under the baseline level according to WHO criteria and after excluding other factors than IDA contributing to anemia. This study reinforces the importance of long‐term follow‐up of the iron status, also in pediatric CD patients.

The most recent ECCO guidelines suggest that after IV iron treatment, re‐treatment should be initiated as soon as serum ferritin drops below 100 μg/L or Hb drops below cutoff level according to WHO criteria [5]. However, the benefit evidence of treating iron deficiency in the absence of anemia in IBD patients and particularly in pediatric IBD patients is yet unavailable. Currently, there are no guidelines concerning the management of ID without anemia in both adult and pediatric IBD patients. However, ID without anemia and IDA should be closely monitored.

The rational of preventing IDA by treating ID relies on the fact that iron is important to cell function and that ID can cause symptoms with a negative impact on the quality of life [5, 18]. Several symptoms have been associated to ID, such as reduced physical performance and cognitive function, fatigue, headache, sleeping disorders, loss of libido, or restless‐legs syndrome among others [47].

The evidence concerning the treatment of ID without anemia in the IBD setting, however, is not yet available. ECCO guidelines recommend that the choice of treating ID without anemia should be considered on an individual basis (according to patients’ past medical history and comorbidities, age group, symptoms, and individual/parental preferences) [5]. Data on the effectiveness of periodic IV iron administration as a prevention of IDA in IBD patients are available for FCM and II (in adult patients) [44–46]. In the adult studies, after IDA treatment with IV iron, patients received regular doses of IV iron (300–500 mg of FCM or II) during a 12‐month period allowing to maintain stable Hb levels without IDA recurrence and with good tolerance regarding side effects.

In refractory cases of ACD with an insufficient response to intravenous iron and despite optimized IBD, therapy ECCO guidelines propose that these patients may be considered for erythropoiesis‐stimulating agent treatment. The recommendation is supported by studies demonstrating the improvement of Hb levels; follow‐up data, however, are lacking and these agents should be used with caution [5]. There are no pediatric data on the use of erythropoiesis‐stimulating agents in IBD patients.

Red blood cell transfusion may be considered when Hb concentration is below 7 g/dL, or above if symptoms or particular risk factors are present. ECCO guidelines also recommend that blood transfusions should be followed by subsequent intravenous iron supplementation [5].

7. Final comments and future prospectives

In conclusion, the current management of IBD‐A represents a paradigm shift in clinical practice, involving several specific challenges. A pro‐active approach is recommended, and both adult and pediatric IBD patients should be regularly assessed for the presence of anemia, because of its high prevalence, impact on quality of life, and comorbidity.

Although both oral and IV formulations have demonstrated efficacy in IBD‐A, oral iron might not be an ideal treatment for active IBD‐A, with gastrointestinal intolerance occurring in many patients and a long course needed to resolve anemia and replenish stores. Nonadherence to a prescribed course of oral iron is common, and even in adherent patients, poor intestinal absorption fails to compensate for iron need in the presence of ongoing blood losses. In addition, studies in animal models do not exclude the possibility that oral iron formulations might increase disease activity in IBD and even the risk of development of colorectal cancer.

IV iron treatment has shown to be safe and well tolerated in IBD patients with good clinical response in different formulations (prolonged response). However, although the safety of IV iron has been demonstrated in studies comprising thousands of patients with numerous clinical entities associated with ID, safety concerns still exist. All iron products can cause hypersensitivity or other reactions and the comparative frequencies of reactions remain unknown. All involved clinicians should acquaint with the incidence, clinical nature, and significance of reactions to the existing preparations, systematically reporting to a central agency.

Although any IV iron can cause acute severe reactions, the incidence and severity of reactions seem quite low, with the doses commonly administered in clinical practice and currently available dextran‐free formulations of intravenous iron (as iron gluconate, IO, and FCM). Similarly, concerns about IV iron therapy potentially increasing the risks for infections and cardiovascular disease have not been confirmed in prospective studies or clinical trials and remain largely unproven hypothesis. There remain, however, some concerns about the potential for long‐term harm from repeated iron administration.

Sound data are still lacking, on when to stop iron supplementation therapy in order to avoid iron overloading, which may cause side effects, because of the potential of the metal to catalyze the formation of toxic radicals. Recent guidelines on the management of anemia in dialysis patients suggest that ferritin levels of up to 500 ng/mL appear to be safe and this limit might be a useful upper threshold in the management of patients with IBD‐A. Interestingly, in a recently published prospective single‐center study, iron supplementation in chronic kidney disease patients was associated with a significant reduction in overall mortality.

Certainly, the control of inflammation is a key objective in the treatment of IBD. Because IDA has a considerable impact on patient quality of life, a thorough and complete diagnostic and therapeutic strategy should be followed to help patients attain as normal a life as possible. Given the novel intravenous iron‐replacement regimens introduced within the last 10 years, physicians may have some doubts concerning the optimal iron‐replacement regimen to be prescribed. Based on the current evidence and guidelines, oral iron therapy should be preferred for patients with mild IDA in quiescent disease stages unless they are intolerant or have an inadequate response, whereas IV iron supplementation may be advantageous in patients with more severe IDA or flaring IBD, because inflammation compromises intestinal iron absorption.

Further well‐designed clinical trials, including well‐selected patients and clearly detailing primary and secondary outcomes, are warranted, to optimize the treatment schedule in these patients. In particular, considering the small number of published randomized controlled studies in this important area, prospective studies will be necessary to establish the optimal dose for correction and maintenance of target Hb levels and iron stores (definition of clinical end point) and to clarify the impact of anemia correction and iron supplementation on the course of IBD‐A and patient outcomes. Ideally, these clinical trials should integrate new surrogate biomarkers, reflecting more precisely the true systemic iron pathways.

Also, prospective clinical trials are needed to better define the clinical and hematological long‐term outcomes in patients with IBD‐A. In fact, good‐quality data are required both in adults and in children, demonstrating the efficacy, safety, and tolerance profile of different available iron formulas (oral and IV) in IBD‐IDA, as well as to determine their cost‐efficacy ratio.

The importance of long‐term follow‐up of the iron status in IBD patients, including in those in remission and/or with mild disease, should also be emphasized, as well as the inclusion of quality of life impact as a relevant specific intervention outcome. Finally, the future acquisition of larger pediatric experience in the field will drive the emergence of evidence‐based‐specific pediatric guidelines.

In summary, all clinicians (particularly gastroenterologists) treating patients with IBD will need to be increasingly aware of the importance of the screening, diagnosis, and management specificities of anemia and IBD, for improvement in their general well‐being, a matter which frequently does not yet gain the required attention. With the new generation of available iron compounds and existent guidelines, the ultimate goal will be the improvement of the patients’ quality of life.