European Journal of Cardiovascular Medicine

Inflammatory Bowel Disease (IBD), encompassing Crohn's disease (CD) and Ulcerative Colitis (UC), is a group of chronic, immune-mediated inflammatory disorders of the gastrointestinal tract [1]. While gastrointestinal symptoms are prominent, IBD is a systemic condition associated with numerous extraintestinal manifestations, of which anemia is the most frequent [2]. The prevalence of anemia in IBD patients is reported to be between 17% and 74%, varying widely depending on the study population, disease activity, and the diagnostic criteria used [3]. This common comorbidity significantly impacts patients' health-related quality of life, increases hospitalization rates, and is associated with greater disease severity [4].

The pathophysiology of anemia in IBD is multifactorial and complex. The primary mechanisms are iron deficiency anemia (IDA) and anemia of chronic disease (ACD) [5]. IDA results from a combination of chronic gastrointestinal blood loss, impaired dietary iron absorption in the inflamed proximal small bowel (particularly in CD), and inadequate dietary intake [6]. ACD, on the other hand, is driven by the systemic inflammatory state characteristic of IBD. Pro-inflammatory cytokines, such as interleukin-6 (IL-6), stimulate hepatic production of hepcidin, the master regulator of iron homeostasis. Hepcidin blocks intestinal iron absorption and promotes iron sequestration within the reticuloendothelial system, rendering iron unavailable for erythropoiesis despite adequate body stores [7, 8]. In many IBD patients, these two mechanisms coexist, leading to a mixed-type anemia that presents a diagnostic and therapeutic challenge [9].

Recent studies have highlighted the persistent under-diagnosis and under-treatment of anemia in the IBD population, despite clear international guidelines recommending proactive screening and management [10]. For instance, a large European cohort study demonstrated that while anemia was highly prevalent, a significant proportion of patients did not receive appropriate iron therapy or evaluation [11]. Furthermore, distinguishing between IDA and ACD is critical, as their management strategies differ, yet traditional iron biomarkers like ferritin can be unreliable in the context of inflammation, where it acts as an acute-phase reactant [12].

While the general mechanisms of IBD-associated anemia are well-established, there remains a gap in understanding the specific prevalence and distribution of anemia subtypes within local patient populations. Such data are crucial for tailoring institutional protocols for screening, diagnosis, and treatment. Therefore, the aim of this study was to evaluate the prevalence of anemia in a well-characterized cohort of IBD patients at a tertiary medical center, to delineate the subtypes of anemia, and to identify the clinical and biochemical factors associated with its presence.

Inclusion and Exclusion Criteria

Patients aged 18 years or older with a confirmed diagnosis of either Crohn's disease or Ulcerative Colitis, based on standard endoscopic, histological, and radiological criteria, were eligible for inclusion. To be included, patients must have had a complete blood count (CBC), iron studies (serum ferritin, transferrin saturation), and C-reactive protein (CRP) measured within a four-week period.

Exclusion criteria were: (1) presence of other known causes of chronic anemia (e.g., chronic kidney disease stage 4-5, hematological malignancies, thalassemia); (2) major surgery or blood transfusion within the three months prior to laboratory assessment; (3) active non-IBD-related bleeding; (4) pregnancy; and (5) use of erythropoiesis-stimulating agents.

A total of 250 patients (130 with CD, 120 with UC) met the eligibility criteria and were included in the final analysis.

Data Collection

Data were systematically extracted from patient records and entered into a secure database. The following variables were collected:

• Demographics: Age, sex.
• Clinical Characteristics: IBD type (CD or UC), disease location, disease duration (years since diagnosis).
• Disease Activity: Disease activity was assessed clinically at the time of laboratory testing. For CD, the Harvey-Bradshaw Index (HBI) was used, with HBI ≥5 defining active disease. For UC, the Simple Clinical Colitis Activity Index (SCCAI) was used, with SCCAI ≥3 defining active disease.
• Laboratory Parameters: Hemoglobin (Hb, g/dL), mean corpuscular volume (MCV, fL), serum ferritin (ng/mL), transferrin saturation (TSAT, %), and C-reactive protein (CRP, mg/L).

Definitions

• Anemia: Defined according to World Health Organization (WHO) criteria as Hb <13 g/dL for males and Hb <12 g/dL for females.
• Anemia Subtypes: Based on iron studies and CRP levels, anemic patients were categorized as follows:
• Iron Deficiency Anemia (IDA): Anemia with serum ferritin <30 ng/mL.
• Anemia of Chronic Disease (ACD): Anemia with serum ferritin ≥100 ng/mL and TSAT <20%.
• Mixed-type Anemia (IDA+ACD): Anemia with serum ferritin between 30 and 100 ng/mL and TSAT <20%.

Statistical Analysis
All statistical analyses were performed using SPSS software, version 27.0 (IBM Corp., Armonk, NY). Continuous data were presented as mean ± standard deviation (SD), while categorical data were presented as numbers and percentages (n, %). The normality of continuous data was assessed using the Shapiro-Wilk test. To compare anemic and non-anemic groups, the independent samples t-test was used for normally distributed continuous variables, and the Mann-Whitney U test was used for non-normally distributed variables. The Chi-square (χ²) test or Fisher’s exact test was used for categorical variables. A p-value of less than 0.05 was considered statistically significant.

Patient Characteristics and Prevalence of Anemia
A total of 250 IBD patients were included, with a mean age of 42.1 ± 13.5 years; 52.0% (n=130) were male. The cohort comprised 130 (52.0%) patients with CD and 120 (48.0%) with UC. The overall prevalence of anemia in the study population was 40.0% (n=100). Anemia was significantly more common in patients with CD (47.7%, 62/130) compared to those with UC (31.7%, 38/120) (p=0.012).

Comparison between Anemic and Non-Anemic Patients
The baseline demographic and clinical characteristics of patients stratified by anemia status are presented in Table 1. Patients in the anemic group were of similar age and sex distribution to those in the non-anemic group. However, anemic patients had a significantly longer mean disease duration (8.9 ± 4.1 vs. 6.2 ± 3.5 years, p<0.001). Furthermore, anemia was strongly associated with active disease. Among anemic patients, 78.0% (78/100) had active disease, compared to only 30.0% (45/150) in the non-anemic group (p<0.001). This was reflected in significantly higher mean CRP levels in the anemic cohort (25.4 ± 12.1 mg/L) compared to the non-anemic cohort (8.2 ± 4.5 mg/L) (p<0.001).

Table 1. Baseline Characteristics of IBD Patients Stratified by Anemia Status.

*p-values <0.05 are in bold. SD: standard deviation; CRP: C-reactive protein.

Subtypes of Anemia
Among the 100 patients with anemia, the most prevalent subtype was IDA (n=55, 55.0%), followed by mixed-type anemia (n=25, 25.0%) and ACD (n=20, 20.0%). The distribution of anemia subtypes differed between CD and UC patients, as detailed in Table 2. Although IDA was the most common type in both groups, a higher proportion of CD patients exhibited IDA compared to UC patients (61.3% vs. 44.7%), while a greater proportion of UC patients had ACD (26.3% vs. 16.1%). However, this difference in subtype distribution between CD and UC did not reach statistical significance (p=0.189).

Table 2. Distribution of Anemia Subtypes in IBD Patients.

*p-value for the comparison of subtype distribution between Crohn's Disease and Ulcerative Colitis. IDA: Iron Deficiency Anemia; ACD: Anemia of Chronic Disease.

Laboratory Parameters across Anemia Subtypes
Table 3 shows a comparison of key hematological and biochemical markers across the three anemia subtypes. As expected, patients with IDA had the lowest mean hemoglobin, MCV, ferritin, and TSAT levels. Conversely, patients with ACD had the highest mean ferritin levels (185.4 ± 55.2 ng/mL) despite low TSAT, indicative of iron sequestration. CRP levels were highest in the ACD group (35.1 ± 10.5 mg/L), followed by the mixed-type group, and were lowest in the IDA group, highlighting the strong correlation between inflammation and the ACD phenotype. All inter-group differences for the listed parameters were statistically significant (p<0.001).

Table 3. Laboratory Parameters According to Anemia Subtype.

*p-value for the overall comparison across the three groups (ANOVA). MCV: Mean Corpuscular Volume; TSAT: Transferrin Saturation.

This study provides a comprehensive evaluation of anemia in a tertiary care IBD cohort, revealing a significant prevalence of 40.0%. This finding aligns with the wide range reported in the literature and emphasizes that anemia remains a major clinical issue in IBD management [3, 4]. The higher prevalence of anemia observed in patients with CD (47.7%) compared to UC (31.7%) is also consistent with previous research [13]. This difference is likely attributable to the pathophysiology of CD, which often involves the small bowel, leading to greater malabsorption of iron and other micronutrients, in addition to chronic inflammation and potential bleeding [6].

A key finding of our study is the strong association between anemia and both disease activity and inflammation. Anemic patients had markedly higher CRP levels and were far more likely to have clinically active disease. This supports the dual pathogenesis of anemia in IBD, where active inflammation not only contributes to blood loss but also directly suppresses erythropoiesis via the hepcidin-mediated pathway of ACD [7, 8]. The significantly longer disease duration in the anemic group suggests that the cumulative burden of chronic inflammation and intermittent blood loss over time contributes to the development and persistence of anemia.

Our analysis of anemia subtypes demonstrates that absolute iron deficiency (IDA) is the predominant cause, accounting for 55% of anemic cases. This underscores the critical importance of evaluating and managing iron status in all IBD patients. However, a substantial portion of patients (45%) presented with anemia driven wholly or in part by inflammation (ACD or mixed-type). This highlights a crucial clinical challenge: the interpretation of iron studies in the setting of inflammation. Ferritin, a standard marker of iron stores, is an acute-phase reactant that can be falsely elevated by inflammation, potentially masking underlying iron deficiency [12]. Our classification, using a ferritin cutoff of <30 ng/mL for absolute ID and considering the 30-100 ng/mL range with low TSAT as mixed-type, is in line with current European guidelines and helps to navigate this diagnostic dilemma [10]. The distinct biochemical profiles seen in Table 3, with the ACD group showing the highest CRP and ferritin levels, validate this approach and reinforce the concept that different pathophysiological mechanisms are at play.

The clinical implications of these findings are significant. First, they reinforce the need for diligent, routine anemia screening in all IBD patients, particularly those with CD or evidence of active disease. Second, the diagnostic workup should not rely on a single marker but must include a full iron panel (ferritin and TSAT) interpreted in the context of an inflammatory marker like CRP. This comprehensive assessment is essential for distinguishing IDA from ACD or mixed-type anemia, which in turn guides appropriate therapy. While oral iron may suffice for mild IDA in patients with quiescent disease, patients with active inflammation or those with features of ACD may not absorb oral iron effectively and are prime candidates for intravenous iron therapy, which bypasses intestinal absorption and can more rapidly replete iron stores [14, 15]. Furthermore, effective control of the underlying intestinal inflammation is paramount for resolving the ACD component and improving erythropoiesis [9].

This study has several limitations. Its retrospective design relies on the accuracy and completeness of medical records and may be subject to selection bias. We could not assess the contribution of other micronutrient deficiencies, such as vitamin B12 and folate, which can also cause anemia in IBD. Furthermore, disease activity was based on clinical scores, and endoscopic data were not uniformly available for all patients at the time of the laboratory tests. Finally, being a single-center study, our findings may not be generalizable to all IBD populations. Future prospective studies are needed to confirm these associations and to evaluate the efficacy of different anemia management strategies based on subtype characterization.

In conclusion, this study confirms that anemia is a highly prevalent and significant comorbidity in patients with IBD, affecting 40% of our cohort. Its presence is strongly linked to active disease, higher inflammatory burden, and a longer disease duration, with a higher prevalence in Crohn's disease. While iron deficiency anemia is the most common subtype, a large proportion of patients exhibit anemia related to chronic inflammation. These results underscore the necessity for a proactive and systematic approach to the diagnosis and management of anemia in IBD, utilizing a comprehensive panel of biomarkers to differentiate its underlying causes and to tailor therapy effectively, thereby improving patient outcomes and quality of life.

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